Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1

ABSTRACT

This invention relates to novel compounds of the Formula I, Ik, Iq 1-21 , Ir 1-21 , Is 1-21 , It 1-7 , pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11 β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

RELATED APPLICATIONS

This application is the U.S. National Stage of PCT InternationalApplication Number PCT/US2009/002641, filed Apr. 30, 2009, which claimsthe benefit of U.S. Provisional Application No. 61/206,775, filed onFeb. 4, 2009, U.S. Provisional Application No. 61/137,148, filed on Jul.25, 2008, and U.S. Provisional Application No. 61/049,650, filed May 1,2000.

PCT/US2009/002641 also claims priority to International Application No.PCT/US2008/009017, which designated the United States and was filed onJul. 25, 2008, published in English, which claims the benefit of U.S.Provisional Application No. 61/049,650, filed May 1, 2008.

The entire teachings of the above applications are incorporated hereinby reference.

FIELD OF THE INVENTION

The present invention relates to inhibitors of 11β-hydroxysteroiddehydrogenase type 1 (11β-HSD1), pharmaceutical compositions thereof andmethods of using the same.

BACKGROUND OF THE INVENTION

Glucocorticoids, such as cortisol (hydrocortisone), are steroid hormonesthat regulate fat metabolism, function and distribution, and play a rolein carbohydrate, protein and fat metabolism. Glucocorticoids are alsoknown to have physiological effects on development, neurobiology,inflammation, blood pressure, metabolism, and programmed cell death.Cortisol and other corticosteroids bind both the glucocorticoid receptor(GR) and the mineralocorticoid receptor (MR), which are members of thenuclear hormone receptor superfamily and have been shown to mediatecortisol function in vivo. These receptors directly modulatetranscription via DNA-binding zinc finger domains and transcriptionalactivation domains.

Until recently, the major determinants of glucocorticoid action wereattributed to three primary factors: (1) circulating levels ofglucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal(HPA) axis); (2) protein binding of glucocorticoids in circulation; and(3) intracellular receptor density inside target tissues. Recently, afourth determinant of glucocorticoid function has been identified:tissue-specific pre-receptor metabolism by glucocorticoid-activating and-inactivating enzymes. These 11β-hydroxysteroid dehydrogenase (11β-HSD)pre-receptor control enzymes modulate activation of GR and MR byregulation of glucocorticoid hormones. To date, two distinct isozymes of11-beta-HSD have been cloned and characterized: 11β-HSD1 (also known as11-beta-HSD type 1, 11betaHSD1, HSD11B1, HDL, and HSD11L) and 11β-HSD2.11β-HSD1 is a bi-directional oxidoreductase that regenerates activecortisol from inactive 11-keto forms, whereas 11β-HSD2 is aunidirectional dehydrogenase that inactivates biologically activecortisol by converting it into cortisone.

The two isoforms are expressed in a distinct tissue-specific fashion,consistent with the differences in their physiological roles. 11β-HSD1is widely distributed in rat and human tissues; expression of the enzymeand corresponding mRNA have been detected in human liver, adiposetissue, lung, testis, bone and ciliary epithelium. In adipose tissue,increased cortisol concentrations stimulate adipocyte differentiationand may play a role in promoting visceral obesity. In the eye, 11β-HSD1may regulate intraocular pressure and may contribute to glaucoma; somedata suggest that inhibition of 11β-HSD1 may cause a drop in intraocularpressure in patients with intraocular hypertension (Kotelevstev et al.(1997), Proc. Natl. Acad. Sci. USA 94(26):14924-9). Although 11β-HSD1catalyzes both 11-beta-dehydrogenation and the reverse 11-oxoreductionreaction, 11β-HSD1 acts predominantly as a NADPH-dependent oxoreductasein intact cells and tissues, catalyzing the formation of active cortisolfrom inert cortisone (Low et al. (1994) J. Mol. Endocrin. 13: 167-174).In contradistinction, 11β-HSD2 expression is found mainly inmineralocorticoid target tissues such as kidney (cortex and medulla),placenta, sigmoid and rectal colon, salivary gland and colonicepithelial cell lines. 11β-HSD2 acts as an NAD-dependent dehydrogenasecatalyzing the inactivation of cortisol to cortisone (Albiston et al.(1994) Mol. Cell. Endocrin. 105: R11-R17), and has been shown to protectthe MR from glucocorticoid excess (e.g., high levels of receptor-activecortisol) (Blum, et al. (2003) Prog. Nucl. Acid Res. Mol. Biol.75:173-216).

Mutations in either the 11β-HSD1 or the 11β-HSD2 genes result in humanpathology. For example, individuals with mutations in 11β-HSD2 aredeficient in this cortisol-inactivation activity and, as a result,present with a syndrome of apparent mineralocorticoid excess (alsoreferred to as ‘SAME’) characterized by hypertension, hypokalemia, andsodium retention (Edwards et al. (1988) Lancet 2: 986-989; Wilson et al.(1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Similarly, mutations in11β-HSD1 and in the gene encoding a co-localized NADPH-generatingenzyme, hexose 6-phosphate dehydrogenase (H6PD), can result in cortisonereductase deficiency (CRD); these individuals present with ACTH-mediatedandrogen excess (hirsutism, menstrual irregularity, hyperandrogenism), aphenotype resembling polycystic ovary syndrome (PCOS) (Draper et al.(2003) Nat. Genet. 34: 434-439).

Notably, disruption of homeostasis in the HPA axis by either deficientor excess secretion or action results in Cushing's syndrome or Addison'sdisease, respectively (Miller and Chrousos (2001) Endocrinology andMetabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4^(th) Ed.:387-524). Patients with Cushing's syndrome or receiving glucocorticoidtherapy develop reversible visceral fat obesity. The phenotype ofCushing's syndrome patients closely resembles that of Reaven's metabolicsyndrome (also known as Syndrome X or insulin resistance syndrome), thesymptoms of which include visceral obesity, glucose intolerance, insulinresistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven(1993) Ann. Rev. Med. 44: 121-131). Although the role of glucocorticoidsin human obesity is not fully characterized, there is mounting evidencethat 11β-HSD1 activity plays an important role in obesity and metabolicsyndrome (Bujalska et al. (1997) Lancet 349: 1210-1213); (Livingstone etal. (2000) Endocrinology 131: 560-563; Rask et al. (2001) J. Clin.Endocrinol. Metab. 86: 1418-1421; Lindsay et al. (2003) J. Clin.Endocrinol. Metab. 88: 2738-2744; Wake et al. (2003) J. Clin.Endocrinol. Metab. 88: 3983-3988).

Data from studies in mouse transgenic models supports the hypothesisthat adipocyte 11β-HSD1 activity plays a central role in visceralobesity and metabolic syndrome (Alberts et al. (2002) Diabetologia.45(11): 1526-32). Over-expression in adipose tissue of 11β-HSD1 underthe control of the aP2 promoter in transgenic mice produced a phenotyperemarkably similar to human metabolic syndrome (Masuzaki et al. (2001)Science 294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112:83-90). Moreover, the increased activity of 11β-HSD1 in these mice isvery similar to that observed in human obesity (Rask et al. (2001) J.Clin. Endocrinol. Metab. 86: 1418-1421). In addition, data from studieswith 11β-HSD1-deficient mice produced by homologous recombinationdemonstrate that the loss of 11β-HSD1 leads to an increase in insulinsensitivity and glucose tolerance due to a tissue-specific deficiency inactive glucocorticoid levels (Kotelevstev et al. (1997) Proc. Natl.Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276:41293-41300; Morton et al. (2004) Diabetes 53: 931-938).

The published data supports the hypothesis that increased expression of11β-HSD1 contributes to increased local conversion of cortisone tocortisol in adipose tissue and hence that 11β-HSD1 plays a role in thepathogenesis of central obesity and the appearance of the metabolicsyndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9-17).Therefore, 11β-HSD1 is a promising pharmaceutical target for thetreatment of the metabolic syndrome (Masuzaki, et al., (2003) Curr. DrugTargets Immune Endocr. Metabol. Disord. 3: 255-62). Furthermore,inhibition of 11β-HSD1 activity may prove beneficial in treatingnumerous glucocorticoid-related disorders. For example, 11β-HSD1inhibitors could be effective in combating obesity and/or aspects of themetabolic syndrome cluster, including glucose intolerance, insulinresistance, hyperglycemia, hypertension, and/or hyperlipidemia(Kotelevstev et al. (1997) Proc. Natl. Acad. Sci. 94: 14924-14929;Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al.(2004) Diabetes 53: 931-938). In addition, inhibition of 11β-HSD1activity may have beneficial effects on the pancreas, including theenhancement of glucose-stimulated insulin release (Billaudel and Sutter(1979) Horm. Metab. Res. 11: 555-560; Ogawa et al. (1992) J. Clin.Invest. 90: 497-504; Davani et al. (2000) J. Biol. Chem. 275:34841-34844).

Furthermore, given that inter-individual differences in generalcognitive function have been linked to variability in the long-termexposure to glucocorticoids (Lupien et al. (1998) Nat. Neurosci. 1:69-73) and dysregulation of the HPA axis resulting in chronic exposureto glucocorticoid excess in certain brain subregions has been theorizedto contribute to the decline of cognitive function (McEwen and Sapolsky(1995) Curr. Opin. Neurobiol. 5: 205-216), one might predict thatinhibition of 11β-HSD1 could reduce exposure to glucocorticoids in thebrain and thereby protect against deleterious glucocorticoid effects onneuronal function, including cognitive impairment, dementia, and/ordepression. Notably, it is known that stress and glucocorticoidsinfluence cognitive function (de Quervain et al. (1998) Nature 394:787-790); and it has been shown that 11β-HSD1, through its control ofglucocorticoid action in the brain, may have effects on neurotoxicity(Rajan et al. (1996) Neuroscience 16: 65-70; Seckl (2000)Neuroendocrinol. 18:49-99).

There is also evidence that glucocorticoids and 11β-HSD1 play a role inregulation of in intra-ocular pressure (IOP) (Stokes et al. (2000)Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest.Ophthalmol. Vis. Sci. 42: 2037-2042); if left untreated, elevated IOPcan lead to partial visual field loss and eventually blindness. Thus,inhibition of 11β-HSD1 in the eye could reduce local glucocorticoidconcentrations and IOP, and 11β-HSD1 hence could potentially be used totreat glaucoma and other visual disorders.

Transgenic aP2-11βHSD1 mice exhibit high arterial blood pressure andhave increased sensitivity to dietary salt. Moreover, plasmaangiotensinogen levels are elevated in the transgenic mice, as areangiotensin II and aldosterone; and treatment of the mice with anangiotensin II antagonist alleviates the hypertension (Masuzaki et al.(2003) J. Clinical Invest. 112: 83-90). This suggests that hypertensionmay be caused or exacerbated by 11β-HSD1 activity. Thus, 11β-HSD1inhibitors may be useful for treatment of hypertension andhypertension-related cardiovascular disorders. Inhibition of 11β-HSD1 inmature adipocytes is also expected to attenuate secretion of plasminogenactivator inhibitor 1 (PAI-1), which is an independent cardiovascularrisk factor (Halleux et al. (1999) J. Clin. Endocrinol. Metabl. 84:4097-4105).

Glucocorticoids can have adverse effects on skeletal tissues; andprolonged exposure to even moderate glucocorticoid doses can result inosteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81:3441-3447). In addition, 11β-HSD1 has been shown to be present incultures of human primary osteoblasts as well as cells from adult bone(Cooper et al. (2000) Bone 27: 375-381), and the 11β-HSD1 inhibitorcarbenoxolone has been shown to attenuate the negative effects ofglucocorticoids on bone nodule formation (Bellows et al. (1998) Bone 23:119-125). Thus, inhibition of 11β-HSD1 is predicted to decrease thelocal glucocorticoid concentration within osteoblasts and osteoclasts,thereby producing beneficial effects in various forms of bone disease,including osteoporosis.

11β-HSD1 inhibitors may also be useful for immunomodulation. Althoughglucocorticoids are perceived to suppress the immune system, inactuality, there is a complex, dynamic interaction between the HPA axisand the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl.13: 576-581). Glucocorticoids play a role in modulating the balancebetween cell-mediated and humoral immune response, with highglucocorticoid activity normally associated with a humoral response.Inhibition of 11β-HSD1 therefore can be used a means of shifting theimmune response towards a cell-mediated response. Certain diseasestates, such as tuberculosis, leprosy (Hansen's disease) and psoriasis,trigger immune responses that are biased towards a humoral responsewhereas the more effective immune response may be a cell-mediatedresponse. Hence, 11β-HSD1 inhibitors may be useful for treating suchdiseases.

It has been reported that glucocorticoids inhibit wound healing,especially in diabetic patients with ulcers (Bitar et al. (1999) J.Surg. Res. 82: 234-243; Bitar et al. (1999) Surgery 125: 594-601; Bitar(2000) Surgery 127: 687-695; Bitar (1998) Am. J. Pathol. 152: 547-554).Patients that exhibit impaired glucose tolerance and/or type 2 diabetesoften also have impaired wound healing. Glucocorticoids have been shownto increase the risk of infection and delay wound healing (Anstead(1998) Adv. Wound Care 11:277-285). Moreover, there is a correlationbetween elevated levels of cortisol in wound fluid and non-healingwounds (EP Patent App. No. 0 902 288). Recent published patentapplications have suggested that certain 11β-HSD1 inhibitors may beuseful for promoting wound healing (PCT/US2006/043,951).

As evidenced herein, there is a continuing need for new and improveddrugs that inhibit 11β-HSD1. The novel compounds of the instantinvention are effective inhibitors of 11β-HSD1.

SUMMARY OF THE INVENTION

It has now been found that compounds of Formula I or pharmaceuticallyacceptable salts thereof, are effective inhibitors of 11β-HSD1.

The invention is a compound represented by Formula (I)

or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

In a first embodiment of the invention, Formula I and its constituentmembers are defined herein as follows:

R¹ is (a) absent or (b) is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₃)alkoxy(C₁-C₃)alkoxy, or (C₁-C₃)alkoxy(C₁-C₃)alkyland is optionally substituted with up to four groups independentlyselected from fluorine, cyano, oxo, R⁴, R⁴O—, (R⁴)₂N—, R⁴O₂C—, R⁴S,R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—, (R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—,(R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—, (R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—,(R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—, (R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—,R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—, R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—,R⁴OS(═O)₂NHC(═O)—, R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—,(R⁴)₂NS(═O)₂NHC(═O)—, (R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—,R⁴C(═O)NHS(═O)₂—, R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—,R⁴OC(═O)NHS(═O)₂—, R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—,(R⁴)₂NC(═O)NHS(═O)₂—, (R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—,heterocyclyl, heteroaryl, arylamino and heteroarylamino;

A¹ is (a) a bond, or (b) (C₁-C₃)alkylene, CH₂CH₂O, wherein the oxygen isattached to Cy¹, or CH₂C(═O), wherein the carbonyl carbon is attached toCy¹;

Cy¹ is aryl, heteroaryl, monocyclic cycloalkyl or monocyclicheterocyclyl and is optionally substituted with 1 to 4 groupsindependently selected from fluorine, chlorine, bromine, iodine, cyano,nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl,(C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkyl-alkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkyl-alkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl;

Cy² in Formula I is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, thiazolyl or thiadiazoly and is optionally substituted with 1to 4 groups independently selected from fluorine, chlorine, bromine,iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl,hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl,halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl,(C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy,halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy,(C₁-C₆)alkylthio, (C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio,halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkythio,halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl,(C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl,halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl,halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl,(C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkyl-alkanesulfonyl,halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl,halo(C₄-C₇)cycloalkyl-alkanesulfonyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl;

E is (a) a bond or (b) (C₁-C₃)alkylene or (C₁-C₂)alkylenyloxy, whereinthe O is attached to R², each of which is optionally substituted with 1to 4 groups independently selected from methyl, ethyl, trifluoromethylor oxo;

R² is (C₁-C₆)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and isoptionally substituted with up to 4 groups independently selected fromfluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl;

R³ is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₅)cycloalkyl(C₁-C₄)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkoxy, or(C₁-C₃)alkoxy(C₁-C₃)alkyl and is optionally substituted with up to fourgroups independently selected from fluorine, cyano, oxo, R⁴, R⁴O—,(R⁴)₂N—, R⁴O₂C—, R⁴C(═O)O—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—,(R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—,(R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—,(R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—,R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—,R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—,(R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—,R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—,R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—,(R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, spirocycloalkyl;heterocyclyl (which in turn may be optionally substituted with alkyl,haloalkyl, halogen or oxo), heteroaryl (which in turn may be optionallysubstituted with alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl,halogen, trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂,N-monoalkyl-substituted amido, N,N-dialkyl-substituted amido, or oxo),arylamino (which in turn may be optionally substituted with alkyl,alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl,dialkylamino, nitro, cyano, CO₂H, CONH₂, N-monoalkyl-substituted amidoand N,N-dialkyl-substituted amido) and heteroarylamino (which in turnmay be optionally substituted with alkyl, haloalkyl, alkoxy, alkylthio,alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro, cyano,CO₂H, CONH₂, N-monoalkyl-substituted amido, N,N-dialkyl-substitutedamido, or oxo); and

R⁴ is independently selected from H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl and(C₁-C₆)alkoxy(C₁-C₆)alkyl.

Alternatively, the first embodiment above excludes the compounds ofstructural formulas PR-205, PR-211, PR-214, PR-222, PR-225, PR-235,PR-236, PR-281, PR-292, PR-295, PR-298, PR-300, PR-302, PR-305, PR-304,PR-306, PR-307, PR-210, PR-296, PR-311, PR-230, PR-244, PR-258 andPR-291 or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

Alternatively, the first embodiment above excludes the compounds ofstructural formulas PR-205, PR-211, PR-214, PR-222, PR-225, PR-235,PR-236, PR-281, PR-292, PR-295, PR-298, PR-300, PR-302, PR-305, PR-304,PR-306, PR-307, PR-210, PR-296, PR-311, PR-230, PR-244, PR-258 andPR-291, or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof, and the compound of Example 32, Example 33,(R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-(2-aminoethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-allyl-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid,3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid,(R)-6-allyl-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-allyl-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-3-((S)-1-(4-(1H-pyrazol-3-yl)phenyl)ethyl)-6-allyl-6-phenyl-1,3-oxazinan-2-one,or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

Another embodiment of the invention is a pharmaceutical compositioncomprising i) a pharmaceutically acceptable carrier or diluent, and ii)a compound of Formulas I, Ik, Iq¹⁻²¹, Ir¹⁻²¹, Is¹⁻²¹ or It¹⁻⁷, or apharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is a method of inhibiting 11β-HSD1activity comprising the step of administering to a mammal in need ofsuch treatment an effective amount of a compound of Formulas I, Ik,Iq¹⁻²¹, Ir¹⁻²¹, Is¹⁻²¹ or It¹⁻⁷, or a pharmaceutically acceptable salt,enantiomer or diastereomer thereof.

Another embodiment of the invention is a method of treating a subjectwith a disease associated with the activity or expression of 11β-HSD1,comprising the step of administering to the subject an effective amountof a compound of Formulas I, Ik, Iq¹⁻²¹, Ir¹⁻²¹, Is¹⁻²¹ or It¹⁻⁷, or apharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Another embodiment of the invention is the use of a compound of FormulasI, Ik, Iq¹⁻²¹, Ir¹⁻²¹, Is¹⁻²¹ or It¹⁻⁷, or a pharmaceutically acceptablesalt, enantiomer or diastereomer thereof for the manufacture of amedicament for inhibiting 11β-HSD1 activity in a mammal in need of suchtreatment.

Another embodiment of the invention is the use of a compound of FormulasI, Ik, Iq¹⁻²¹, Ir¹⁻²¹, Is¹⁻²¹ or It¹⁻⁷, or a pharmaceutically acceptablesalt, enantiomer or diastereomer thereof for the manufacture of amedicament for treating a subject with a disease associated with theactivity or expression of 11β-HSD1.

Another embodiment of the invention is a compound of Formulas I, Ik,Iq¹⁻²¹, Ir¹⁻²¹, Is¹⁻²¹ or It¹⁻⁷, or a pharmaceutically acceptable salt,enantiomer or diastereomer thereof for use in inhibiting 11β-HSD1activity in a mammal in need of such treatment.

Another embodiment of the invention is a compound of I, Ik, Iq¹⁻²¹,Ir¹⁻²¹, Is¹⁻²¹ or It¹⁻⁷, or a pharmaceutically acceptable salt,enantiomer or diastereomer thereof for use in for treating a subjectwith a disease associated with the activity or expression of 11β-HSD1.

DETAILED DESCRIPTION OF THE INVENTION

Another embodiment of the invention is a compound of Formula Ik:

or a pharmaceutically acceptable salt thereof;

R^(1a) is absent or is methyl or ethyl;

Cy² is pyridyl, thiazolyl or pyrazolyl and is optionally substituted by1 to 4 groups independently selected from halo, hydroxy, methoxy,hydroxymethyl, methoxycarbonyl, amino, carbamoyl, methylcarbamoyl,dimethylcarbamoyl, (2-methoxyethyl)aminocarbonyl, acetylaminomethyl,methylsulfonyl, methylsulfonylamino, methylaminosulfonyl,isopropylaminosulfonyl, dimethylaminosulfonyl, pyrrolidine-1-sulfonyl,methylsulfonylaminomethyl, tetrazolyl, methyl, trifluoromethyl, acetyl,2-hydroxyethyl and 1-aminoethyl;

R² is phenyl, thienyl, pyridyl or isopropyl each optionally substitutedwith halo, methyl, methylthio or (4-morpholino)methyl; and

R³ is methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl eachoptionally substituted with up to two groups independently selected fromMethyl, HO—, MeO—, H₂N—, MeC(═O)NH—, MeS(═O)₂NH—, H₂NC(═O)—, MeNHC(═O)—,HO₂C—, (HO)₂P(═O)O—, H₂NS(═O)₂O—, H₂NS(═O)₂NH—, MeNHC(═O)NH—,MeNHC(═O)O—, oxo, cyano, HO₂C—, HOCH₂CH₂NH—, 4-morpholino,HOCH₂C(═O)NH—, H₂NCH₂C(═O)NH—, EtNHC(═O)NH, MeOC(═O)NH—,MeNHC(═NC≡N)NH—, Me-, MeS—, MeSO₂— MeSO₂N(Me)—, MeS(═O)₂NHC(═O)—,imidazolylamino-, imidazolyl, tetrazolyl, H₂NCONH—, H₂NCO₂—, HOCH₂CH₂O—,MeNH—, Me₂N— and MeCONMe.

Another embodiment of the invention is a compound of Formula Ik, or apharmaceutically acceptable salt, enantiomer or diastereomer thereof;R^(1a) is absent or is methyl or ethyl; Cy² is optionally substitutedpyridazinyl or pyrimidinyl; R² is (C₁-C₆)alkyl, aryl, heteroaryl,cycloalkyl or heterocyclyl and is optionally substituted with up to 4groups independently selected from fluorine, chlorine, bromine, iodine,cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl,hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl,halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl,(C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy,halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy,(C₁-C₆)alkylthio, (C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio,halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkythio,halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl,(C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl,halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl,halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl,(C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkyl-alkanesulfonyl,halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl,halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and(C₁-C₆)alkylcarbonyl; and R³ is as defined above in the firstembodiment.

Another embodiment of the invention is a compound of any one of FormulasIq¹⁻²¹ or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof:

In Formulas Iq¹⁻²¹, the pyridine, pyridazine, pyrimidine, pyrazine,pyrazole, thiazole and thiadiazole rings are optionally substituted(substitution at ring carbons bonded to hydrogen and ring nitrogen atomsbonded to hydrogen atoms are encompassed, i.e., a “substitutable ringnitrogen atom”) with up to four substituents as described for Cy² in thefirst embodiment. Suitable substituents for Cy² and suitable values forR¹, R², R³, A¹, Cy¹ and E are as defined above in the first embodiment.Alternatively, suitable substituents for Cy¹ and the pyridine,pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazolerings in Formulas Iq¹⁻²¹ are independently fluorine, chlorine, bromine,iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl,hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl,halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl,(C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy,halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy,(C₁-C₆)alkylthio, (C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio,halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkythio,halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl,(C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl,halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl,halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl,(C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkyl-alkanesulfonyl,halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl,halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; and values for R¹, R², R³,A¹, Cy¹ and E are as defined above in the first embodiment.Alternatively, suitable substituents for Cy¹ include (C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen, cyano andnitro; suitable substituents for a substitutable ring nitrogen atom inthe pyrazole rings in Formulas Iq¹⁸, Iq²⁰ and Iq²¹ include (C₁-C₄)alkyl,(C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, and (C₁-C₄)haloalkyl;suitable substituents for a ring carbon atom in the pyridine,pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazolerings in Formulas Iq¹⁻²¹ include fluorine, chlorine, cyano, amino,(C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, CONH₂,(C₁-C₄)alkylaminocarbonyl, di(C₁-C₄)alkylaminocarbonyl,(C₃-C₄)cycloalkylaminocarbonyl,{(C₁-C₄)alkyl}{(C₃-C₄)cycloalkyl}aminocarbonyl and(C₁-C₄)alkylcarbonylamino; the ring nitrogen in the pyridine rings inFormulas Iq¹⁻⁴ is optionally substituted by oxo; and suitable values forR¹, R², R³, A¹, Cy¹ and E are as defined the first embodiment. Inanother alternative, the embodiments in this paragraph exclude thefollowing compounds:

(S)-6-(2-hydroxyethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

3-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine1-oxide

(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3

(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

-   (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

(R)-6-allyl-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

(R)-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

3-(4-((S)-1-((R)-6-(3-amino-3-oxopropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine1-oxide

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(5-methoxypyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

3-((R)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide

(R)-6-allyl-3-((S)-1-(4-(5-chloropyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

N-(2-((S)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)ethyl)methanesulfonamide

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

(R)-6-allyl-3-((S)-1-(4-(2,4-dimethylthiazol-5-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one

and

(R)-3-((S)-1-(4-(1H-pyrazol-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

For each of the embodiments described in the previous paragraph, R¹ ispreferably methyl or ethyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Iq¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Iq¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ isH₂NC(═O)CMe₂CH₂, hydroxy-3-methyl butyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Iq¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl optionally substituted with 1, 2 or 3 substituents selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Iq¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl optionally substituted with 1, 2 or 3 substituents selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Iq¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ is2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Iq¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiments described in the paragraph immediatelyfollowing Formulas Iq¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine,pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazolerings in Formulas Iq¹⁻²¹ are optionally substituted with fluoro, chloro,cyano, CONH₂, CONHMe, CONMe₂, CONHc-Pr, methoxy, ethoxy, methyl, ethylor CF₃. the substitutable ring nitrogen atom in the pyrazole rings inFormulas Iq¹⁸, Iq²⁰ and Iq²¹ are optionally substituted with(C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, or(C₁-C₂)haloalkyl, the ring nitrogen in the pyridine rings in FormulasIq¹⁻⁴ is optionally substituted by oxo.

Another embodiment of the invention is a compound of any one of FormulasIr¹⁻²¹, or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof:

In Formulas Ir¹⁻²¹, the pyridine, pyridazine, pyrimidine, pyrazine,pyrazole, thiazole and thiadiazole rings are optionally substituted(substitution at ring carbons bonded to hydrogen and ring nitrogen atomsbonded to hydrogen atoms are encompassed, i.e., a “substitutable ringnitrogen atom”) with up to four substituents as described for Cy² in thefirst embodiment. Suitable substituents for Cy² and suitable values forR¹, R², R³, Cy¹ and E are as defined above in the first embodiment.Alternatively, suitable substituents for Cy¹ and the pyridine,pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazolerings in Formulas Ir¹⁻²¹ are independently fluorine, chlorine, bromine,iodine, cyano, nitro, amino, hydroxy, carboxy, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, hydroxy(C₃-C₆)cycloalkyl,(C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, halo(C₂-C₆)alkenyl,hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl(C₂-C₄)alkynyl,halo(C₁-C₆)alkyl, halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl,(C₁-C₆)alkoxy, (C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy,halo(C₁-C₆)alkoxy, halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy,(C₁-C₆)alkylthio, (C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio,halo(C₁-C₆)alkylthio, halo(C₃-C₆)cycloalkythio,halo(C₄-C₇)cycloalkylalkylthio, (C₁-C₆)alkanesulfinyl,(C₃-C₆)cycloalkanesulfinyl, (C₄-C₇)cycloalkylalkanesulfinyl,halo(C₁-C₆)alkanesulfinyl, halo(C₃-C₆)cycloalkanesulfinyl,halo(C₄-C₇)cycloalkylalkanesulfinyl, (C₁-C₆)alkanesulfonyl,(C₃-C₆)cycloalkanesulfonyl, (C₄-C₇)cycloalkyl-alkanesulfonyl,halo(C₁-C₆)alkanesulfonyl, halo(C₃-C₆)cycloalkanesulfonyl,halo(C₄-C₇)cyclo-alkylalkanesulfonyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; and values for R¹, R², R³,Cy¹ and E are as defined above in the first embodiment. Alternatively,suitable substituents for Cy¹ include (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen, cyano and nitro; suitablesubstituents for a substitutable ring nitrogen atom in the pyrazolerings in Formulas Ir¹⁸, Ir²⁰ and Ir²¹ include (C₁-C₄)alkyl,(C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, and (C₁-C₄) haloalkyl;suitable substituents for a ring carbon atom in the pyridine,pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazolerings in Formulas Ir¹⁻²¹ include fluorine, chlorine, cyano, hydroxy,amino, (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, CONH₂,(C₁-C₄)alkylaminocarbonyl, di(C₁-C₄)alkylaminocarbonyl,(C₃-C₄)cycloalkylaminocarbonyl,{(C₁-C₄)alkyl}{(C₃-C₄)cycloalkyl}aminocarbonyl and(C₁-C₄)alkylcarbonylamino; the ring nitrogen in pyridines Ir¹⁻⁴ isoptionally substituted by oxo; and suitable values for R¹, R², R³, Cy¹and E are as defined above in the first embodiment. In anotheralternative, the embodiments described in this paragraph exclude thecompounds PR-205, PR-211, PR-214, PR-222, PR-225, PR-235, PR-236,PR-281, PR-292, PR-295, PR-298, PR-300, PR-302, PR-305, PR-304, PR-306,PR-307, PR-210, PR-296, PR-311, PR-230, PR-244, PR-258 and PR-291 or apharmaceutically acceptable salt, enantiomer or diastereomer thereof.

Alternatively, the first embodiment above excludes the compounds ofstructural formulas PR-205, PR-211, PR-214, PR-222, PR-225, PR-235,PR-236, PR-281, PR-292, PR-295, PR-298, PR-300, PR-302, PR-305, PR-304,PR-306, PR-307, PR-210, PR-296, PR-311, PR-230, PR-244, PR-258 andPR-291, or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof, and the compound of Example 32, Example 33,(R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-(2-aminoethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-allyl-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid,3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid,(R)-6-allyl-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-allyl-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-3-((S)-1-(4-(1H-pyrazol-3-yl)phenyl)ethyl)-6-allyl-6-phenyl-1,3-oxazinan-2-one,or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

For each of the embodiment described in the previous paragraph, R¹ ispreferably methyl or ethyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ir¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ir¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ir¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl optionally substituted with 1, 2 or 3 substituents selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ir¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl optionally substituted with 1, 2 or 3 substituents selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ir¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ is2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ir¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Ir¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine,pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazolerings in Formulas Ir¹⁻²¹ are optionally substituted with fluoro, chloro,cyano, CONH₂, CONHMe, CONMe₂, CONHc-Pr, methoxy, ethoxy, methyl, ethylor CF₃. the substitutable ring nitrogen atom in the pyrazole rings inFormulas Ir¹⁸, Ir²⁰ and Ir²¹ are optionally substituted with(C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, or(C₁-C₂)haloalkyl, the ring nitrogen in the pyridine rings in FormulasIr¹⁻⁴ is optionally substituted by oxo.

Another embodiment of the invention is a compound of any one of FormulasIs¹⁻²¹, or a pharmaceutically acceptable salt thereof:

In Formulas Is¹⁻²¹, the pyridine, pyridazine, pyrimidine, pyrazine,pyrazole, thiazole and thiadiazole rings in Formulas Is¹⁻²¹ areoptionally substituted (substitution at ring carbons bonded to hydrogenand ring nitrogen atoms bonded to hydrogen atoms are encompassed, i.e.,a “substitutable ring nitrogen atom”) with up to four substituents asdescribed for Cy² in the first embodiment. Suitable values for G¹ arefluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkyl-alkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkyl-alkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; n is 0, 1 or 2;substituents for Cy² and suitable values for R¹, R² and R³ are asdefined above in the first embodiment. Alternatively, n is 0, 1 or 2,suitable values for G¹ in Formulas Is¹⁻²¹ and suitable substituents forthe pyridine, pyridazine, pyrimidine, pyrazine, pyrazole, thiazole andthiadiazole rings in Formulas Is¹⁻²¹ are independently fluorine,chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy,(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkyl-alkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkyl-alkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and(C₁-C₆)alkylcarbonyl; and values for R¹, R², R³ and E are as definedabove in the first embodiment. Alternatively, n is 0, 1 or 2; suitablevalues for G¹ include (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, cyano and nitro; suitable substituents for asubstitutable ring nitrogen atom in the pyrazole rings in Formulas Is¹⁸,Is²⁰ and Is²¹ include (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl, and (C₁-C₄)haloalkyl; suitablesubstituents for a ring carbon atom in the pyridine, pyridazine,pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings inFormulas Is¹⁻²¹ include fluorine, chlorine, cyano, amino, (C₁-C₄)alkyl,(C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl, (C₃-C₄)cycloalkylaminocarbonyl,{(C₁-C₄)alkyl}{(C₃-C₄)cycloalkyl}aminocarbonyl and(C₁-C₄)alkylcarbonylamino; the ring nitrogen in pyridines Is¹⁻⁴ isoptionally substituted by oxo; and suitable values for R¹, R² and R³ areas defined above in the first embodiment. In another alternative, theembodiments described in this paragraph exclude the compounds PR-205,PR-211, PR-214, PR-222, PR-225, PR-235, PR-236, PR-281, PR-292, PR-295,PR-298, PR-300, PR-302, PR-305, PR-304, PR-306, PR-307, PR-210, PR-296,PR-311, PR-230, PR-244, PR-258 and PR-291, or a pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.

Alternatively, the first embodiment above excludes the compounds ofstructural formulas PR-205, PR-211, PR-214, PR-222, PR-225, PR-235,PR-236, PR-281, PR-292, PR-295, PR-298, PR-300, PR-302, PR-305, PR-304,PR-306, PR-307, PR-210, PR-296, PR-311, PR-230, PR-244, PR-258 andPR-291, or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof, and the compound of Example 32, Example 33,(R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-(2-aminoethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-allyl-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid,3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid,(R)-6-allyl-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-allyl-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-3-((S)-1-(4-(1H-pyrazol-3-yl)phenyl)ethyl)-6-allyl-6-phenyl-1,3-oxazinan-2-one,or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

For each of the embodiment described in the previous paragraph, R¹ ispreferably methyl or ethyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Is¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Is¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Is¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl optionally substituted with 1, 2 or 3 substituents selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Is¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl optionally substituted with 1, 2 or 3 substituents selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Is¹⁻²¹, R¹ is preferably methyl or ethyl; and R³ is2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Is¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas Is¹⁻²¹, R¹ is preferably methyl or ethyl; R² isphenyl or fluorophenyl; R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; one or two ring carbon atoms in the pyridine,pyridazine, pyrimidine, pyrazine, pyrazole, thiazole and thiadiazolerings in Formulas Is¹⁻²¹ are optionally substituted with fluoro, chloro,cyano, CONH₂, CONHMe, CONMe₂, CONHc-Pr, methyl, ethyl or CF₃; thesubstitutable ring nitrogen atom in the pyrazole rings in Formulas Is¹⁸,Is²⁰ and Is²¹ is optionally substituted with (C₁-C₄)alkyl,(C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl, or (C₁-C₂)haloalkyl,the ring nitrogen in the pyridine rings in Formulas Is¹⁻⁴ is optionallysubstituted by oxo.

Another embodiment of the invention (referred to herein as the “FirstAlternate Embodiment”) is a compound represented by Structural FormulasIs¹⁻²¹, wherein: n is 0 or 1, preferably 0; each G¹ is independently(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy,halogen, cyano or nitro; the substitutable ring nitrogen atom in thepyrazole rings in Formulas Is¹⁸, Is²⁰ and Is²¹ is substituted withhydroxy(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl ordi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; the pyridine, pyridazine,pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings inFormulas Is¹⁻²¹ are optionally substituted at one or more substitutablering carbon atoms with a group independently selected from fluorine,chlorine, cyano, hydroxy, amino, (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl and (C₁-C₄)alkylcarbonylamino; R¹ is methylor ethyl; R² is phenyl, thienyl, pyridyl or isopropyl each optionallysubstituted with up to three groups independently selected from halo,methyl, methylthio or (4-morpholino)methyl; and R³ is methyl, ethyl,propyl, butyl, vinyl, allyl or ethoxyethyl each optionally substitutedwith up to two groups independently selected from methyl, HO—, MeO—,H₂N—, MeC(═O)NH—, MeS(═O)₂NH—, H₂NC(═O)—, MeNHC(═O)—, HO₂C—,(HO)₂P(═O)O—, H₂NS(═O)₂O—, H₂NS(═O)₂NH—, MeNHC(═O)NH—, MeNHC(═O)O—, oxo,cyano, HO₂C—, HOCH₂CH₂NH—, 4-morpholino, HOCH₂C(═O)NH—, H₂NCH₂C(═O)NH—,EtNHC(═O)NH, MeOC(═O)NH—, MeNHC(═NC≡N)NH—, Me-, MeS—, MeSO₂—MeSO₂N(Me)—, MeS(═O)₂NHC(═O)—, imidazolylamino-, imidazolyl, tetrazolyl,H₂NCONH—, H₂NCO₂—, HOCH₂CH₂O—, MeNH—, Me₂N— and MeCONMe.

Alternatively for Structural Formulas Is¹⁻²¹, R² is phenyl optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed above for the First Alternate Embodiment.

Alternatively for Structural Formulas Is¹⁻²¹, R³ is H₂NC(═O)CMe₂CH₂,3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed above for the First Alternate Embodiment.

Alternatively for Structural Formulas Is¹⁻²¹, R² is phenyl optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed in the First Alternate Embodiment.

Alternatively for Structural Formulas Is¹⁻²¹, R³ is2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder ofthe variables are as described in the First Alternate Embodiment.

Alternatively for Structural Formulas Is¹⁻²¹, R² is phenyl orfluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed in the First Alternate Embodiment.

Alternatively for Structural Formulas Is¹⁻²¹, R² is phenyl orfluorophenyl; R³ is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;one or two substitutable ring carbon atoms in the pyridine, pyridazine,pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings inFormulas Is¹⁻²¹ are optionally substituted with methyl or ethyl; and theremainder of the variables are as described in the First AlternateEmbodiment.

For the embodiment described in the previous seven paragraphs, n is 0and all of the substitutable ring carbons in the pyridine, pyridazine,pyrimidine, pyrazine, pyrazole, thiazole and thiadiazole rings inFormulas Is¹⁻²¹ are preferably unsubstituted.

Another embodiment of the invention is a compound represented by any oneof Formulas It¹⁻⁶, or a pharmaceutically acceptable salt thereof:

In Formulas It¹⁻⁷, G¹ is (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl,(C₁-C₄)haloalkoxy, halogen, cyano and nitro; n is 0 1 or 2; G^(2a) andG^(2b) are independently selected from hydrogen, fluorine, chlorine,cyano, amino, (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl, (C₃-C₄)cycloalkylaminocarbonyl,{(C₁-C₄)alkyl}{(C₃-C₄)cycloalkyl}aminocarbonyl and(C₁-C₄)alkylcarbonylamino; G² is (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl or(C₁-C₄)haloalkyl; and suitable values for R¹, R² and R³ are as definedabove in the first embodiment. In another alternative, the embodimentsin the this paragraph exclude the compounds PR-205, PR-211, PR-214,PR-222, PR-225, PR-235, PR-236, PR-281, PR-292, PR-295, PR-298, PR-300,PR-302, PR-305, PR-304, PR-306, PR-307, PR-210, PR-296, PR-311, PR-230,PR-244, PR-258, and PR-291, or a pharmaceutically acceptable salt,enantiomer or diastereomer thereof.

Alternatively, the first embodiment above excludes the compounds ofstructural formulas PR-205, PR-211, PR-214, PR-222, PR-225, PR-235,PR-236, PR-281, PR-292, PR-295, PR-298, PR-300, PR-302, PR-305, PR-304,PR-306, PR-307, PR-210, PR-296, PR-311, PR-230, PR-244, PR-258 andPR-291, or a pharmaceutically acceptable salt, enantiomer ordiastereomer thereof, and the compound of Example 32, Example 33,(R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-(2-aminoethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-6-allyl-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one,3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid,3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid,(R)-6-allyl-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one,(R)-6-allyl-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,(R)-3-((S)-1-(4-(1H-pyrazol-3-yl)phenyl)ethyl)-6-allyl-6-phenyl-1,3-oxazinan-2-one,or a pharmaceutically acceptable salt, enantiomer or diastereomerthereof.

For each of the embodiment described in the previous paragraph, R¹ ispreferably methyl or ethyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas It¹⁻⁷, R¹ is preferably methyl or ethyl; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas It¹⁻⁷, R¹ is preferably methyl or ethyl; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas It¹⁻⁷, R¹ is preferably methyl or ethyl; R² is phenyloptionally substituted with 1, 2 or 3 substituents selected from halo,cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas It¹⁻⁷, R¹ is preferably methyl or ethyl; R² is phenyloptionally substituted with 1, 2 or 3 substituents selected from halo,cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxyethyl,2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas It¹⁻⁷, R¹ is preferably methyl or ethyl; and R³ is2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.

For each of the embodiment described in the paragraph immediatelyfollowing Formulas It¹⁻⁷, R¹ is preferably methyl or ethyl; R² is phenylor fluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl.

Alternatively, —CHO, NH₂—SO₂NH₂, —COON, and —CONH₂ are excluded aspermissible substituents for the pyridine and thiazole rings at theposition corresponding to Cy² for all of the specific embodimentsdescribed above for Formulas Iq¹⁻²¹, Ip¹⁻²¹, Ir¹⁻²¹, Is¹⁻²¹, and It¹⁻⁷.

Another embodiment of the invention (referred to herein as the “SecondAlternate Embodiment”) is a compound represented by Structural FormulasIt¹⁻⁷, wherein: n is 0 or 1, preferably 0; each G¹ is independently(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy,halogen, cyano or nitro; G^(1a) is hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl ordi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; G^(2b) and G^(2c) areindependently selected from hydrogen, fluorine, chlorine, cyano,hydroxy, amino, (C₁-C₄)alkyl, (C₃-C₄)cycloalkyl,(C₃-C₄)cycloalkyl(C₁-C₂)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkoxy, CONH₂, (C₁-C₄)alkylaminocarbonyl,di(C₁-C₄)alkylaminocarbonyl and (C₁-C₄)alkylcarbonylamino; R¹ is methylor ethyl; R² is phenyl, thienyl, pyridyl or isopropyl each optionallysubstituted with up to three groups independently selected from halo,methyl, methylthio or (4-morpholino)methyl; and R³ is methyl, ethyl,propyl, butyl, vinyl, allyl or ethoxyethyl each optionally substitutedwith up to two groups independently selected from methyl, HO—, MeO—,H₂N—, MeC(═O)NH—, MeS(═O)₂NH—, H₂NC(═O)—, MeNHC(═O)—, HO₂C—,(HO)₂P(═O)O—, H₂NS(═O)₂O—, H₂NS(═O)₂NH—, MeNHC(═O)NH—, MeNHC(═O)O—, oxo,cyano, HO₂C—, HOCH₂CH₂NH—, 4-morpholino, HOCH₂C(═O)NH—, H₂NCH₂C(═O)NH—,EtNHC(═O)NH, MeOC(═O)NH—, MeNHC(═NC≡N)NH—, Me-, MeS—, MeSO₂—MeSO₂N(Me)—, MeS(═O)₂NHC(═O)—, imidazolylamino-, imidazolyl, tetrazolyl,H₂NCONH—, H₂NCO₂—, HOCH₂CH₂O—, MeNH—, Me₂N— and MeCONMe.

Alternatively for Structural Formulas It¹⁻⁷, R² is phenyl optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed above for the Second Alternate Embodiment.

Alternatively for Structural Formulas It¹⁻⁷, R³ is H₂NC(═O)CMe₂CH₂,3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed above for the Second Alternate Embodiment.

Alternatively for Structural Formulas It¹⁻⁷, R² is phenyl optionallysubstituted with 1, 2 or 3 substituents independently selected fromhalo, cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isH₂NC(═O)CMe₂CH₂, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed in the Second Alternate Embodiment.

Alternatively for Structural Formulas It¹⁻⁷, R³ is2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder ofthe variables are as described in the Second Alternate Embodiment.

Alternatively for Structural Formulas It¹⁻⁷, R² is phenyl orfluorophenyl; and R³ is 2-hydroxy-2-methylpropyl or2-cyano-2-methylpropyl; and the remainder of the variables are asdescribed in the Second Alternate Embodiment.

Alternatively for Structural Formulas It¹⁻⁷, R² is phenyl orfluorophenyl; R³ is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;one or two substitutable ring carbon atoms in the oxodihydropyridylrings are optionally substituted with methyl or ethyl; and the remainderof the variables are as described in the Second Alternate Embodiment.

For the embodiment described in the previous seven paragraphs, n is 0and G^(2b) and G^(2c) are preferably —H.

Compounds of the invention are also disclosed in INHIBITORS OF11β-HYDROXYSTEROID DEHYDOGENASE I, U.S. Provisional Application No.61/61/135,933, filed Jul. 25, 2008; Cyclic Inhibitors Of11β-Hydroxysteroid Dehydrogenase 1, U.S. Provisional Application No.61/135,933, filed May 1, 2008; Cyclic Inhibitors Of 11β-HydroxysteroidDehydrogenase 1, U.S. Provisional Application No. 61/137,148, filed Jul.25, 2008; and Cyclic Inhibitors Of 11β-Hydroxysteroid Dehydrogenase 1,International Application No. PCT/US2008/009017, filed Jul. 25, 2008;the entire teachings of these applications are incorporated herein byreference in their entirety.

Definitions

The term “alkyl” means a straight or branched hydrocarbon radical having1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term “cycloalkyl” means a monocyclic, bicyclic or tricyclic,saturated hydrocarbon ring having 3-10 carbon atoms and includes, forexample, cyclopropyl (c-Pr), cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl,spiro[4.4]nonane, adamantyl and the like.

The term “aryl” means an aromatic radical which is a phenyl group, anaphthyl group, an indanyl group or a tetrahydronaphthalene group. Anaryl group is optionally substituted with 1-4 substituents. Exemplarysubstituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen,trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂,N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido.

The term “heteroaryl” means a 5- and 6-membered heteroaromatic radicalwhich may optionally be fused to a saturated or unsaturated ringcontaining 0-4 heteroatoms selected from N, O, and S and includes, forexample, a heteroaromatic radical which is 2- or 3-thienyl, 2- or3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-,or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl,1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 2-, 3-, 4-, 5-,6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-,4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, 4-, or5-imidazolyl. A heteroaryl is optionally substituted. Exemplarysubstituents include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen,trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂,N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido, or byoxo to form an N-oxide.

The term “heterocyclyl” means a 4-, 5-, 6- and 7-membered saturated orpartially unsaturated heterocyclic ring containing 1 to 4 heteroatomsindependently selected from N, O, and S. Exemplary heterocyclyls includepyrrolidine, pyrrolidin-2-one, 1-methylpyrrolidin-2-one, piperidine,piperidin-2-one, dihydropyridine, tetrahydropyridine, piperazine,1-(2,2,2-trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine,1,4-dihydro-4-oxopyridine, piperazin-2-one,3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine,tetrahydrofuran, tetrahydropyran, tetrahydrothiophene,tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane,1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-one,imidazolidin-2-one, imidazolidine-2,4-dione,tetrahydropyrimidin-2(1H)-one, morpholine, N-methylmorpholine,morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine1,1-dioxide, tetrahydro-1,2,5-thiaoxazole 1,1-dioxide,tetrahydro-2H-1,2-thiazine 1,1-dioxide, hexahydro-1,2,6-thiadiazine1,1-dioxide, tetrahydro-1,2,5-thiadiazole 1,1-dioxide isothiazolidine1,1-dioxide, 6-oxo-1,6-dihydropyridazin-3-yl,6-oxo-1,6-dihydropyridazin-4-yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yland 5-oxo-4,5-dihydro-1H-imidazol-2-yl. A heterocyclyl can be optionallysubstituted with 1-4 substituents. Exemplary substituents include alkyl,haloalkyl, halogen and oxo.

The term “spirocycloalkyl” means a cycloalkyl group which shares onering carbon with another alkyl or cycloalkyl group.

As used herein the terms “subject” and “patient” may be usedinterchangeably, and means a mammal in need of treatment, e.g.,companion animals (e.g., dogs, cats, and the like), farm animals (e.g.,cows, pigs, horses, sheep, goats and the like) and laboratory animals(e.g., rats, mice, guinea pigs and the like). Typically, the subject isa human in need of treatment.

When a disclosed compound or its pharmaceutically acceptable salt isnamed or depicted by structure, it is to be understood that solvates orhydrates of the compound or its pharmaceutically acceptable salts arealso included. “Solvates” refer to crystalline forms wherein solventmolecules are incorporated into the crystal lattice duringcrystallization. Solvate may include water or nonaqueous solvents suchas ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc.Solvates, wherein water is the solvent molecule incorporated into thecrystal lattice, are typically referred to as “hydrates.” Hydratesinclude stoichiometric hydrates as well as compositions containingvariable amounts of water. Some of the compounds disclosed in theexemplification may be in the anhydrous form.

The term “compound” also includes labeling at one or more positions withdeuterium. “Labeled with deuterium at a position” means that the amountdeuterium at the position is greater than the amount that is present atnatural abundance. In certain instances, the deuterium at each positionin a “compound” is at natural abundance.

Certain of the disclosed compounds may exist in various stereoisomericforms. Stereoisomers are compounds that differ only in their spatialarrangement. Enantiomers are pairs of stereoisomers whose mirror imagesare not superimposable, most commonly because they contain anasymmetrically substituted carbon atom that acts as a chiral center.“Enantiomer” means one of a pair of molecules that are mirror images ofeach other and are not superimposable. Diastereomers are stereoisomersthat are not related as mirror images, most commonly because theycontain two or more asymmetrically substituted carbon atoms. The symbol“*” in a structural formula represents the presence of a chiral carboncenter. “R” and “S” represent the configuration of substituents aroundone or more chiral carbon atoms. Thus, “R*” and “S*” denote the relativeconfigurations of substituents around one or more chiral carbon atoms.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity;i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H)on each side of a carbon-carbon double bond may be in an E (substituentsare on opposite sides of the carbon-carbon double bond) or Z(substituents are oriented on the same side) configuration.

“R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicateconfigurations relative to the core molecule.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

When the stereochemistry of a disclosed compound is named or depicted bystructure, the named or depicted stereoisomer is at least 60%, 70%, 80%,90%, 99% or 99.9% by weight pure relative to the other stereoisomers.When a single enantiomer is named or depicted by structure, the depictedor named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight optically pure. Percent optical purity by weight is the ratio ofthe weight of the enantiomer over the weight of the enantiomer plus theweight of its optical isomer.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry, and the compound has at least one chiralcenter, it is to be understood that the name or structure encompassesone enantiomer of compound free from the corresponding optical isomer, aracemic mixture of the compound and mixtures enriched in one enantiomerrelative to its corresponding optical isomer.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry and has at least two chiral centers, itis to be understood that the name or structure encompasses adiastereomer free of other diastereomers, a pair of diastereomers freefrom other diastereomeric pairs, mixtures of diastereomers, mixtures ofdiastereomeric pairs, mixtures of diastereomers in which onediastereomer is enriched relative to the other diastereomer(s) andmixtures of diastereomeric pairs in which one diastereomeric pair isenriched relative to the other diastereomeric pair(s).

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of the invention refer to non-toxic “pharmaceuticallyacceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable basic/cationic salts include, the sodium,potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine,L-lysine, L-arginine, ammonium, ethanolamine, piperazine andtriethanolamine salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, malonate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate,phosphate/diphospate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate,teoclate, tosylate, and triethiodide salts.

The following abbreviations have the indicated meanings:

Abbreviation Meaning A % Area percentage Boc tert-butoxy carbonyl ort-butoxy carbonyl (Boc)₂O di-tert-butyl dicarbonate CbzBenzyloxycarbonyl CbzCl Benzyl chloroformate c-Pr cyclopropyl DASTdiethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCC N,N′-dicyclohexylcarbodiimide DCU N,N′-dicyclohexylurea DIADdiisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride DIEAN,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMFN,N-dimethylformamide DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2,4-DNP2,4-dinitrophenylhydrazine DPTBS Diphenyl-t-butylsilyl dr diastereomerratio EDC•HCl, EDCl 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride Equiv equivalents EtOAc Ethyl acetate Fmoc1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]- Fmoc-OSu1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- pyrrolidinedione h, hrhour(s) HOBt 1-hydroxybenzotriazole HATU2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateKHMDS potassium hexamethyldisilazane LAH or LiAlH₄ lithium aluminumhydride LC-MS liquid chromatography-mass spectroscopy LHMDS lithiumhexamethyldisilazane m-CPBA meta-chloroperoxybenzoic acid Me methyl MsClmethanesulfonyl chloride Min minute MS mass spectrum NaH sodium hydrideNaHCO₃ sodium bicarbonate NaN₃ sodium azide NaOH sodium hydroxide Na₂SO₄sodium sulfate NMM N-methylmorpholine NMP N-methylpyrrolidinonePd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) PE petroleum etherQuant quantitative yield rt room temperature Satd saturated SOCl₂thionyl chloride SFC supercritical fluid chromatography SPAscintillation proximity assay SPE solid phase extraction TBAFtetrabutylammonium fluoride TBS t-butyldimethylsilyl TBDPSt-butyldiphenylsilyl TBSCl t-butyldimethylsilyl chloride TBDPSClt-butyldiphenylsilyl chloride TEA triethylamine or Et₃N TEMPO2,2,6,6-tetramethyl-1-piperidinyloxy free radical Teoc1-[2-(trimethylsilyl)ethoxycarbonyloxy]- Teoc-OSu1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5- dione T_(ext)External temperature T_(int) Internal temperature TFA trifluoroaceticacid Tlc, TLC thin layer chromatography TMS trimethylsilyl TMSClchlorotrimethylsilane or trimethylsilyl chloride t_(R) retention timeTsOH p-toluenesulfonic acid

General Description of Synthetic Methods

Compounds of Formula I* can be prepared by several processes. In thediscussion below, A¹, Cy¹, E, R¹, R², R³, Y and n have the meaningsindicated above unless otherwise noted. Cy² is an optionally substitutedpyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiadiazolyl, thiazolyl orpyrazolyl group. In cases where the synthetic intermediates and finalproducts of Formula I* described below contain potentially reactivefunctional groups, for example amino, hydroxyl, thiol and carboxylicacid groups, that may interfere with the desired reaction, it may beadvantageous to employ protected forms of the intermediate. Methods forthe selection, introduction and subsequent removal of protecting groupsare well known to those skilled in the art. (T. W. Greene and P. G. M.Wuts “Protective Groups in Organic Synthesis” John Wiley & Sons, Inc.,New York 1999). Such protecting group manipulations are assumed in thediscussion below and not described explicitly. Generally, reagents inthe reaction schemes are used in equimolar amounts; however, in certaincases it may be desirable to use an excess of one reagent to drive areaction to completion. This is especially the case when the excessreagent can be readily removed by evaporation or extraction. Basesemployed to neutralize HCl in reaction mixtures are generally used inslight to substantial excess (1.05-5 equivalents).

In a first process a compound of Formula I*, can be prepared by reactionof an aminoalcohol intermediate of Formula II with a reagent of FormulaIII, wherein Z¹ and Z² are leaving groups such as chloride, 1-imidazolylor aryloxide in an inert solvent such as THF, CH₂Cl₂, toluene or MeCN,usually in the presence of an organic or inorganic base such astriethylamine or NaHCO₃ respectively, at −10° C. to 120° C.:

Certain instances of reagent III are especially convenient because theyare commercially available. For example when Z¹ and Z² are bothchloride, III is phosgene. When Z¹ and Z² are both 1-imidazolyl, III iscarbonyl diimidazole. When Z¹ is chloride and Z² is p-nitrophenoxide,III is p-nitrophenyl chloroformate. When Z¹ and Z² are both OCCl₃, IIIis triphosgene and as little as one third of molar equivalent can beused.

Aminoalcohol intermediates of Formula II can be prepared by reduction ofamides of Formula IV using a hydride reagent such as BH₃.THF solution,BH₃.Me₂S or LiAlH₄ in an inert solvent ethereal such as THF or DME at20° C. to 100° C. for between 1 h and 48 h:

Intermediates of Formula IV can be prepared by coupling of aβ-hydroxyacid of Formula V with an amine of Formula VI using standardpeptide coupling reagents such as EDC in the presence of HOBt andN,N-diisopropylethylamine in an inert solvent such as CH₂Cl₂ at 0-30° C.for between 1 h and 24 h:

Amine intermediates of Formula VI, wherein A¹=CH₂ and R¹ is absent, canbe prepared by reduction of amides of Formula VII using a hydridereagent such as BH₃.THF solution, BH₃.Me₂S or LiAlH₄ in an inert solventethereal such as THF or DME at 20° C. to 100° C. for between 1 h and 48h:

Amine intermediates of Formula VI, wherein A¹ is a bond, R¹ is absentand Cy¹ is not an aromatic or heteroaromatic ring, can be prepared fromketones of formula VIII via oximes of Formula IX or by reductiveamination of a ketone of Formula VIII with ammonia:

Methods for the conversion of ketones to oximes are described in Smith,M. B. and March, J. “March's Advanced Organic Chemistry” pp 1194-1195,5^(th) Edition, Wiley, New York, N.Y., 2001. Methods for the reductionof oximes to primary amines are described in Smith, M. B. and March, J.“March's Advanced Organic Chemistry” p 1555, 5^(th) Edition, Wiley, NewYork, N.Y., 2001. Methods for the reductive amination of ketones aredescribed in Baxter, E. W. and Reitz, A. B. “Organic Reactions” Volume59, Ed. Overman, L. E., Wiley Interscience, 2002.

Similarly amine intermediates of Formula VI, wherein A¹ is CH and R¹ ismethyl or ethyl, can be prepared by reduction t-butylsulfinylimines ofFormula VIIIb which can be prepared from ketones of Formula VIIIa andt-butylsulfinamide or by addition of organometallic reagents of FormulaR¹M, wherein R¹ is Me or Et and M is Li, MgCl, MgBr or MgI, tot-butylsulfinylimines of Formula VIIId which can be prepared fromaldehydes of Formula VIIIc.

High stereoselectivity is often achieved in such reactions using chiralt-butylsulfinylimines.

Intermediates of Formula II, wherein n=0, can be prepared by reaction ofoxetanes of Formula X with amines of Formula VI as described in Smith,M. B. and March, J. “March's Advanced Organic Chemistry” p 505, 5^(th)Edition, Wiley, New York, N.Y. 2001:

Intermediates of Formula II can also be prepared by reductive aminationof β-hydroxyaldehydes of Formula Xa with amines of Formula VI. Methodsfor the reductive amination of aldehydes are described in Baxter, E. W.and Reitz, A. B. “Organic Reactions” Volume 59, Ed. Overman, L. E.,Wiley Interscience, 2002.

Aldehydes of Formula Xa can be prepared from homoallylic alcohols ofFormula XXI by treatment with Os₄ and NalO₄.

Intermediates of Formula II can also be prepared by reaction of aminesof Formula VI with haloalcohols of Formula XXX or sulfonates of FormulaXVII.

Intermediates of Formula II, wherein A¹=CH₂ and R¹ is absent, can beprepared by reduction of amide intermediates of formula XI using ahydride reagent such as BH₃.THF solution, BH₃.Me₂S or LiAlH₄ in an inertsolvent ethereal such as THF or DME at 20° C. to 100° C. for between 1 hand 48 h:

Amide intermediates of Formula XI can be prepared by reaction of anaminoalcohol intermediate of Formula XII with activated carboxylic acidof Formula XIII wherein Z³=chloride or an activated ester, such as anN-hydroxysuccinimide ester:

Amino-alcohol intermediates of Formula XII, wherein n=0, can be preparedby reaction of an epoxide of Formula XIV with cyanide ion followed byreduction of the resulting hydroxynitrile of Formula XV with hydrogengas in the presence of a catalyst or with a hydride source such asLiAlH₄:

Epoxide compounds of formula XIV can, in turn, be prepared in a numberof ways including, as described in Aube, J. “Epoxidation and RelatedProcesses” Chapter 3.2 in Volume 1 of “Comprehensive Organic Synthesis”Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, PergamonPress, New York, 1992.

Hydroxynitrile intermediates of Formula XV can be prepared by treatmentof ketones of Formula XVI with acetonitrile anion, formed by treatmentof acetonitrile with n-BuLi or LDA, in an inert, anhydrous solvent suchas THF at low temperature:

Amino-alcohol intermediates of Formula XII, wherein n is 0, can beprepared by treatment of sulfonate intermediates of Formula XVII,wherein R^(A) is for example methyl, trifluoromethyl or p-methylphenyl,with ammonia:

Amino-alcohol intermediates of Formula XII can be prepared by treatmentof sulfonate intermediates of Formula XVII with sodium azide to give anazide intermediate of Formula XVIII, followed by catalytic hydrogenationor by Staudinger reduction with PPh₃ in wet THF:

Sulfonate intermediates of Formula XVII can be prepared from diolintermediates of Formula XIX with a sulfonyl chloride R^(A)SO₂Cl:

Diol intermediates of Formula XIX can be prepared by hydroboration ofallyl alcohols of Formula XX:

Diol intermediates of Formula XIX can be prepared by ozonolysis andreduction of homoallyl alcohols of Formula XXI:

Aminoalcohol intermediates of Formula II, wherein A¹ is a bond, R¹ isabsent, and Cy¹ is a heteroaryl group or an aryl group bearing at leastone strongly electron withdrawing group such as CF₃, can be prepared byreaction of an aminoalcohol intermediate of Formula XII with a compoundof Formula XXII, wherein Cy¹ is a heteroaryl group or an aryl groupbearing at least one strongly electron withdrawing group such as CF₃ andR^(B) is a leaving group such a fluoro, chloro, bromo or iodo:

Aminoalcohol intermediates of Formula II, wherein A¹ is (C₁)alkylene canbe prepared by reaction of an aminoalcohol of Formula XII with analdehyde or methyl ketone of Formula XII in the presence of a reducingagent such as NaCNBH₃ or Na(OAc)₃BH:

Methods for the reductive amination of aldehydes and ketones aredescribed in Baxter, E. W. and Reitz, A. B. “Organic Reactions” Volume59, Ed. Overman, L. E., Wiley Interscience, 2002.

In a second process a compound of Formula I* can be prepared by reactionof a ketocarbamate of Formula XXIV, wherein R^(D) is alkyl or arylalkylgroup such as methyl, t-butyl or benzyl, with an organometallic reagentof Formula XXV wherein M includes, but is not limited to, MgCl, MgBr,MgI or Li:

In specific examples, organometallic reagent XXV is allylmagnesiumbromide, allylzinc(II) bromide, (2-methylallyl)magnesium chloride or(2-methoxy-2-oxoethyl)zinc(II) bromide. In certain cases when M is MgCl,MgBr or MgI, it is advantageous to add CeCl₃ to the reaction mixture.

Ketocarbamates of Formula XXIV can be prepared by reaction ofaminoketones of Formula XXVI with intermediates of Formula XXVII whereinR^(E) is a leaving group such as chloride, succinyloxy, imidazolyl ort-butoxycarboxycarbonyl:

Aminoketones of Formula XXVI, wherein n=0, can be prepared by reactionof α,β-unsaturated ketones of Formula XXVIII with amines of Formula VI:

Aminoketones of Formula XXVI, wherein n=0, can be prepared by reactionof β-dialkylaminoketones of Formula XXVIII, wherein R^(F) is lower alkylespecially methyl, with amines of Formula VI:

β-Dialkylaminoketones of Formula XXVIII are in turn derived fromα,β-unsaturated ketones of Formula XXVII with dialkylamines of FormulaR^(F)NHR^(F).

In a third process a compound of Formula I* can be prepared by reactionof a compound of Formula XVII with an isocyanate of Formula XXIX in thepresence of a base:

Isocyanates of Formula XXIX can be prepared from amines of Formula VI bytreatment with phosgene, diphosgene or triphosgene. This third processis described in greater detail in U.S. Provisional Application Ser. No.61/137,013, filed Jul. 25, 2008 entitled SYNTHESIS OF INHIBITORS OF11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1, the entire teachings of whichare incorporated herein by reference.

In a fourth process a compound of Formula I* can be prepared by reactionof a halo compound of Formula, wherein Hal is chlorine or bromine, withan isocyanate of Formula XXIX in the presence of a base:

Halo compounds of Formula XXX can be prepared by reaction ofβ-haloketones of Formula XXXI with organometallic reagents of FormulaXXV wherein M is a metal containing radical including MgCl, MgBr, MgI orLi. The reaction is optionally carried out in the presence of anhydrouscerium trichloride:

In a fifth process a compound of Formula I*, wherein A¹ is CH₂ or CH₂CH₂and R¹ is absent, can be prepared by reaction of a compound of FormulaXXXII, with a compound of Formula XXXIII, wherein A¹ is CH₂ or CH₂CH₂and R^(G) is a leaving group such as Br, I, OSO₂Me, OSO₂CF₃ or OSO₂Ph,in the presence of a base such as NaH or K₂CO₃:

Compounds of Formula XXXII can be prepared by treatment of compounds ofFormula XII with various reagents of Formula III, wherein Z¹ and Z² areleaving groups such as chloride, 1-imidazolyl or aryloxide in an inertsolvent such as THF, CH₂Cl₂, toluene or MeCN, usually in the presence ofan organic or inorganic base such as triethylamine or NaHCO₃respectively, at −10° C. to 120° C.:

In a sixth process a compound of Formula I*, wherein A¹ is a bond and R1is absent, can be prepared by reaction of a compound of Formula XXXII,with a compound of Formula XXII, wherein R^(B) is a leaving group suchas chloro, bromo, iodo or OSO₂CF₃, in the presence of a base such asK₂CO₃ and a copper or palladium catalyst in an inert solvent such asdioxane, DMF or NMP at elevated temperature:

In a seventh process a compound of Formula I* can be prepared by Suzukicoupling of a compound of Formula XXXIV, wherein Cy¹ is aryl orheteroaryl and R^(X) is bromo, iodo, or trifluoromethanesulfonyloxy,with a boronic acid (R^(Y) is hydrogen) or a boronate ester of FormulaXXXV (R^(Y) is (C₁-C₆)alkyl and the two groups R^(Y) taken together forma (C₁-C₁₂)alkylene group). Alternatively, a compound of Formula XXXIVcan be combined with Cy²-H, wherein the H is replaced with the residueof Formula XXXIV by a transition metal mediated C—H activation process,to yield a compound of general formula 1*. These reactions areparticularly suited for heteroaromatic Cy²-H as detailed in e.g. ChemSus Chem 2008, 1, 404-407, Eur. J. Inorg. Chem. 2008, 2550-59, J. Am.Chem. Soc. 2008, 130, 15185-92, and references quoted therein.

In an eighth process a compound of Formula XXXIV, wherein Cy¹ is aryl orheteroaryl and R^(X) is bromo, iodo, or trifluoromethanesulfonyloxy, canbe reacted with bis(pinacolato)diboron in the presence of a palladiumcatalyst to give a boronate ester of Formula XXXVI which can be furtherreacted with a heterocyclic compound of Formula XXXVII, wherein R^(X) isbromo, iodo, or trifluoromethanesulfonyloxy, again in the presence of apalladium catalyst, to give a compound of Formula I*.

In a ninth process a compound of Formula I* can be prepared from anothercompound of Formula I*. For example:

(1) a compound of Formula I*, wherein R¹ or R³ is ω-hydroxy(C₂-C₆)alkyl,can be oxidized to a compound of Formula I*, wherein R¹ or R³ isω-carboxy(C₁-C₅)alkyl, using Jones reagent.

(2) a compound of Formula I*, wherein R¹ or R³ is ω-carboxy(C₁-C₆)alkyl,can be coupled with ammonia or a (C₁-C₆)alkylamine using a standardpeptide coupling reagent such as EDC to afford a compound of Formula I*,wherein R¹ or R³ is ω-H₂NC(═O)(C₁-C₆)alkyl orω-{(C₁-C₆)alkylNHC(═O)}(C₁-C₆)alkyl.

(3) a compound of Formula I*, wherein R¹ or R³ is ω-hydroxy(C₁-C₆)alkyl,can be converted to its methanesulfonate or trifluoromethanesulfonate,treated with sodium azide and reduced to give a compound of Formula I*,wherein R¹ or R³ is ω-amino(C₁-C₆)alkyl.

(4) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl, canbe reacted with acetic anhydride or acetyl chloride to give a compoundof Formula I*, wherein R¹ or R³ is {acetylamino}(C₁-C₆)alkyl.

(5) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl, canbe reacted with methanesulfonyl chloride to give a compound of FormulaI*, wherein R¹ or R³ is {methanesulfonylamino}(C₁-C₆)alkyl.

(6) a compound of Formula I*, wherein R¹ is (C₂-C₆)alkenyl, ishydroborated to afford a compound of Formula I*, wherein R¹ ishydroxy(C₂-C₆)alkyl.

(7) a compound of Formula I*, wherein R³ is (C₂-C₆)alkenyl, ishydroborated to afford a compound of Formula I*, wherein R³ ishydroxy(C₂-C₆)alkyl.

(8) a compound of Formula I*, wherein R¹ is (C₂-C₆)alkenyl, can bereacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford acompound of Formula I*, wherein R¹ is vicinal dihydroxy(C₂-C₆)alkyl,

(9) a compound of Formula I*, wherein R³ is (C₂-C₆)alkenyl, can bereacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford avicinal diol compound of Formula I*, wherein R³ is vicinaldihydroxy(C₂-C₆)alkyl,

(10) a compound of Formula I*, wherein R¹ is (C₂-C₆)alkenyl, can bereacted with ozone followed by NaBH₄ to give a compound of Formula I*,wherein R¹ is ω-hydroxy(C₁-C₅)alkyl.

(11) a compound of Formula I*, wherein R³ is (C₂-C₆)alkenyl, can bereacted with ozone followed by NaBH₄ to give a compound of Formula I*,wherein R³ is ω-hydroxy(C₁-C₅)alkyl.

(12) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl,can be reacted with an (C₁-C₆)alkyl isocyanate to give a compound ofFormula I*, wherein R¹ or R³ is(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl.

(13) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl,can be reacted with an (C₁-C₆)alkyl chloroformate to give a compound ofFormula I*, wherein R¹ or R³ is (C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkyl.

(14) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl,can be reacted with chlorosulfonyl isocyanate or sulfamide to give acompound of Formula I*, wherein R¹ or R³ isaminosulfonylamino(C₁-C₆)alkyl.

(15) a compound of Formula I*, wherein R¹ or R³ is amino(C₁-C₆)alkyl,can be reacted with a (C₁-C₆)alkylsulfamoyl chloride to give a compoundof Formula I*, wherein R¹ or R³ is(C₁-C₆)alkylaminosulfonylamino(C₁-C₆)alkyl.

(16) a compound of Formula I*, wherein R¹ or R³ is hydroxy(C₁-C₆)alkyl,can be reacted with chlorosulfonyl isocyanate to give a compound ofFormula I*, wherein R¹ or R³ is aminosulfonyloxy(C₁-C₆)alkyl.

(17) a compound of Formula I*, wherein R¹ or R³ is hydroxy(C₁-C₆)alkyl,can be reacted with p-nitrophenyl chloroformate, pentafluorophenylchloroformate or carbonyl diimidazole, followed by ammonia, a(C₁-C₆)alkylamine or a di(C₁-C₆)alkylamine to give a compound of FormulaI*, wherein R¹ or R³ is aminocarboxy(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarboxy(C₁-C₆)alkyl or di(C₁-C₆)alkyl aminocarboxy(C₁-C₆)alkyl.

(18) a compound of Formula I*, wherein R¹ or R³ is hydroxy(C₁-C₆)alkyl,can be reacted with POCl₃ to give a compound of Formula I*, wherein R¹or R³ is (HO)₂P(═O)O(C₁-C₆)alkyl.

(19) a compound of Formula I*, wherein R³ is allyl or homoallyl, can bereacted with oxygen in the presence of PdCl₂ and CuCl to afford acompound of Formula I*, wherein R³ is 2-oxopropyl or 3-oxobutylrespectively.

(20) a compound of Formula I*, wherein R³ is 2-oxopropyl or 3-oxobutyl,can be reacted with MeMgX, wherein X is Cl, Br or I, to give a compoundof Formula I*, wherein R³ is 2-hydroxy-2-methylpropyl or3-hydroxy-3-methylpropyl respectively.

(21) a compound of Formula I*, wherein R³ is —CH₂CO₂Me can be treatedwith MeMgX, wherein X is Cl, Br or I, to give a compound of Formula I*,wherein R³ is 2-hydroxy-2-methylpropyl.

(22) a compound of Formula I*, wherein R³ is allyl or —CH₂C(Me)=CH₂, canbe hydrocyanated with TsCN in the presence of triphenylsilane andvarious cobalt catalysts to afford compounds of Formula I*, wherein R³is —CH₂CH(CN)Me or —CH₂CMe₂CN respectively.

(23) a compound of Formula I*, wherein R³ is CH₂C(Me)₂CN, can be treatedwith acetamide in the presence of PdCl₂ to give a compound of FormulaI*, wherein R³ is CH₂CMe₂CONH₂.

(24) a compound of Formula I*, wherein R³ is —CH₂C(Me)=CH₂ can betreated with m-CPBA followed by lithium triethylborohydride to afford acompound of Formula I*, wherein R³ is 2-hydroxy-2-methylpropyl.

In a tenth process, certain compounds of the invention of Formula I**are prepared as follows:

Halo compounds of Formula LIII can be formed by the treatment ofβ-haloketones of Formula XXXI with organometallic reagents of FormulaLII, wherein M denotes MgCl, MgBr, MgI, ZnBr or ZnI and the reaction isoptionally performed in the presence of anhydrous cerium trichloride inan inert anhydrous solvent, such as tetrahydrofuran, at about −25 to 0°C. for about 0.5 h.

Cyclic carbamates of Formula LIV can be prepared from the reactionbetween β-haloalcohols of Formula LIII where Hal is a chloride andisocyanates of Formula XXXIX in the presence of a base, such as but notlimited to DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in a refluxinginert solvent, such as but not limited to tetrahydrofuran.

Tertiary alcohols of Formula LVII can be derived from trisubstitutedalkenes of Formula LIV by first epoxidizing the alkene with anepoxidation reagent, such as m-CPBA (3-chloroperbenzoic acid), in aninert solvent, such as dichloromethane to produce the correspondingepoxides of Formula LV. The resulting epoxide is then reductively ringopened to provide the corresponding tertiary alcohol I* via treatmentwith a strong hydride reagent, such as lithium triethylborohydride, inan anhydrous inert solvent, such as tetrahydrofuran.

In a variation of the tenth process, a compound of the invention ofFormula I*** is prepared by using a “Suzuki” coupling reaction of aboronate ester of Formula LIX with a haloheterocycle of Formula LX.

The boronate ester of Formula LIX is prepared by reaction of a bromideof Formula LVIII with bis(pinacolato)diboron. LVIII is prepared byepoxidation of alkene LVII, followed by reductive epoxide opening asdescribed above, for 2-methyl-2-hydroxypropyl group is introduced viaepoxidation and hydride ring opening as described above for conversionof LIV to I**.

This tenth process is described in greater detail in U.S. ProvisionalApplication Ser. No. 61/137,013, filed Jul. 25, 2008 entitled SYNTHESISOF INHIBITORS OF 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1, the entireteachings of which are incorporated herein by reference.

LC-MS Methods

Method 1 [LC-MS (3 min)]

Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01%TFA/water, B: 0.01% TFA/CH₃CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 2.0 10 90 2.4 10 90 2.5 90 10 3.0 90 10Method 2 (10-80)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA(1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME(min) A % B %0  90 10 2.2 20 80 2.5 20 80 Flow Rate 1 mL/min Wavelength UV 220 nmOven Temp 50° C. MS ionization ESIMethod 3 (30-90)

Column YMC-PACK ODS-AQ , 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA(1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME(min) A % B %0  70 30 2.2 10 90 2.5 10 90 Flow Rate 1 mL/min Wavelength UV220 OvenTemp 50° C. MS ionization ESI

Preparation 1(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

Method 1

Step 1: (S)-1-bromo-4-(1-isocyanatoethyl)benzene

To a solution of (S)-1-(4-bromophenyl)ethanamine (240 g, 1.2 mol) inmethylene chloride (3 L) and satd aq NaHCO₃ (3 L) solution was addedtriphosgene (118 g, 0.396 mol) at 0° C. The mixture was stirred for 15min. The organic phase was separated, dried over Na₂SO₄ and concentratedto give 1-bromo-4-(1-isocyanato-ethyl)-benzene (170 g, 63%).

Step 2: 1-chloro-3-phenylhex-5-en-3-ol

To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) inanhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1mol/L) at −78° C. under nitrogen. The formed mixture was stirred for 30min at −78° C. The reaction was quenched with aqueous NaHCO₃ solution.The organic phase was separated, dried over Na₂SO₄ and concentrated togive the crude product, which was purified by column chromatography(petroleum ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3-ol(180 g, 86%). ¹H NMR (CDCl₃): 2.27 (m, 2H), 2.51 (m, 1H), 2.74 (m, 1H),3.22 (m, 1H), 3.58 (m, 1H), 5.16 (m, 2H), 5.53 (m, 1H), 7.23 (m, 1H),7.39 (m, 4H).

Step 3:(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

A mixture of 1-chloro-3-phenyl-hex-5-en-3-ol (105 g, 0.050 mmol),(S)-(−)-1-(-bromophenyl)ethyl isocyanate (170 g, 0.752 mol), and DBU(228 g, 1.5 mol) in THF (1700 mL) was heated to reflux overnight. Themixture was diluted with EtOAc and washed with 1N aq HCl. The aqueousphase was extracted with EtOAc (3×). The combined organic phase wasdried over Na₂SO₄. After the solvents were evaporated, the crude productwas purified by column chromatography (petroleum ether/EtOAc=20:1 to5:1) to give(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(100 g, 34%). ¹H NMR (CDCl₃): 1.39 (d, 3H), 2.14 (m, 1H), 2.24 (m, 2H),2.48-2.61 (m, 3H), 2.82 (m, 2H), 5.01 (m, 2H), 5.52 (q, 1H), 5.73 (m,1H), 6.62 (d, 2H), 7.12 (m, 2H), 7.28 (m, 2H).

Step 4:(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-oneand3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(31 g, 78 mmol) and CuCl (19.3 g, 195 mmol) in dry DMF (150 mL) wasadded H₂O (50 mL) and PdCl₂ (4.10 g, 23 mmol) at rt. After addition, themixture was stirred overnight under oxygen. After TLC showed thestarting material had disappeared, the solid was filtered off. Water(200 mL) and EtOAc (200 mL) was added, the organic layers were separatedand the aqueous layer was extracted with EtOAc (3×40 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to give a residue which was purified by columnchromatography (petroleum ether/EtOAc=5:1 to 1:1) to give a mixture of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-oneand3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal,(26 g, 81%).

Step 5:(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one

To a mixture of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-oneand3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanal(20 g, 48.2 mmol) in t-BuOH (250 mL) and 2-methyl-2-butene (50 mL) wasadded a solution of NaClO₂ (19.3 g, 0.213 mol) and NaH₂PO₄ (28 g, 0.179mol) in H₂O (300 mL) at 0° C. The formed mixture was stirred for 1 h at0° C. The mixture was treated with water (100 mL) and extracted withCH₂Cl₂. The combined organic layer was dried over Na₂SO₄, filtered andconcentrated to leave a residue, which was purified by columnchromatography (petroleum ether/EtOAc=5:1 to 2.5:1) to afford(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one(10.0 g, 83%). ¹H NMR (CDCl₃): 1.49 (d, 3H), 2.12 (s, 3H), 2.33 (m, 2H),2.63 (m, 1H), 2.86-3.08 (m, 3H), 5.57 (q, 1H), 6.66 (d, 2H), 7.19 (m,2H), 7.33 (m, 5H).

Step 6:(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one(20 g, 46.4 mmol) in anhydrous THF (200 mL) was added dropwisemethylmagnesium bromide (31 mL, 144 mmol) at −78° C. under nitrogen.Then the mixture was stirred at rt for 1 h. The reaction mixture wasquenched with aq NaHCO₃ (50 mL) under ice water bath. The organic layerswere separated. The aqueous layer was extracted with EtOAc (150 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the crude product, which was purifiedcolumn chromatography (petroleum ether/EtOAc=5:1 to 2:1) to afford(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(13 g, 65%). After re-crystallization from EtOH, 4 g of the purecompound was obtained. ¹H NMR (CDCl₃): 1.06 (s, 3H), 1.12 (s, 3H), 1.44(d, 3H), 2.14 (m, 3H), 2.21 (m, 1H), 2.33 (m, 1H), 2.76 (m, 1H), 5.54(q, 1H), 6.74 (d, 2H), 7.16 (d, 2H), 7.28 (m, 5H).

Alternative Procedure for Method 1 Step 2

A solution of 3-chloro-1-phenylpropan-1-one (100 g, 0.595 mol) in THF(280 ml) was added dropwise to a well-stirred mixture of zinc powder(need not be activated) (40 g, 1.231 mol, satd aq NH₄Cl solution (1500ml) and THF (400 ml). Allyl bromide (143 g, 1.19 mol) was dissolved inTHF (200 ml) was slowly added to the reaction mixture. The reaction wasmildly exothermic, and the mixture began to reflux spontaneously. Afterrefluxing had ceased, the mixture was stirred for 1 h. The mixture wasextracted with EtOAc, dried over anhydrous Na₂SO₄, and concentrated togive 1-chloro-3-phenylhex-5-en-3-ol (122 g, 97%). ¹H NMR: (400 MHz,CDCl₃): δ=2.24 (s, 1H), 2.34 (m, 2H), 2.53 (m, 1H), 2.75 (m, 1H), 3.20(m, 1H), 3.58 (m, 1H), 5.18 (t, 1H), 5.51 (m, 1H), 7.26 (m, 1H),7.26-7.39 (m, 3H).

(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from (S)-1-(4-bromophenyl)propan-1-amine followingprocedures analogous to those described in Preparation 1 Method 1 Steps1 to 3 above.

(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-onewas prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-onefollowing procedures analogous to those described in Preparation 1Method 1 Steps 4 and 6.

Method 2

Step 1. 1-Chloro-5-methyl-3-phenyl-hex-5-en-3-ol

To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in 1500mL of THF (H₂O <100 ppm based on Karl Fischer titration) was charged53.0 mL of 1 M DIBAL-H in hexane under nitrogen at rt. Then3-chloro-2-methylprop-1-ene (160 g, 1.77 mol) was introduced whilemaintaining the internal temperature below 30° C. The resulting solutionwas agitated for 2 h at rt. The solution was titrated in the presence of1.1′-bipyridine to indicate 0.8 M of the corresponding Grignard reagent.To a dry flask containing 307.0 g of anhydrous CeCl₃ (1.25 mol) at rtunder nitrogen was added 1556.8 mL of the Grignard reagent (0.8 M, 1.25mol). The resulting slurry was cooled to −10° C. and agitated for 0.5 h.To the slurry was added 200 g of 3-chloro-1-phenylpropan-1-one (1.19mol) in 200 mL of THF while maintaining the internal temperature below0° C. After the mixture was stirred for 0.5 h, 1200 mL of 1 M aq HCl wasadded to obtain a clear solution while maintaining the internaltemperature below 30° C. After the phase cut, the aqueous layer wasextracted with EtOAc (500 mL). The combined organic layers were washedwith brine and dried over sodium sulfate. Removal of the solvent undervacuum produced crude 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol, whichwas chased with THF to achieve H₂O <500 ppm based on Karl Fischertitration. The crude product (306 g, 83 wt %, 95% yield) was useddirectly in Step 3. ¹H-NMR spectroscopy (500 MHz, CDCl₃) δ 7.38-7.37 (d.J=7.8 Hz, 2H), 7.33 (t, J=7.9 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 4.91 (s,1H), 4.76 (s, 1H), 3.57 (ddd, J=5.6, 10.7, and 10.7, 1H), 3.13 (ddd,J=4.7, 10.7 and 10.7 Hz, 1H), 2.66 (d, J=13.3 Hz, 1H), 2.54 (d, J=11.3Hz, 1H), 2.53 (s, 1H), 2.36 (ddd, J=5.4, 10.6 and 13.9 Hz. 1H), 2.29(ddd, J=5.6, 11.3 and 13.3 Hz, 1H), 1.29 (s, 3H). ¹³C-NMR spectroscopy(125 MHz, CDCl₃) δ 144.3, 141.4, 128.0, 126.6, 124.8, 116.1, 74.2, 51.2,46.0, 39.9, 23.9.

Step 2. 1-Bromo-4-((S)-1-isocyanato-ethyl)-benzene

To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87mol, 2.30 equiv) and 5 L of deionized water. The resulting solution wasagitated for 10-20 min, until the solids dissolved (homogeneous). To theclear solution was charged 250 g (1.25 mol, 1.00 equiv) of(S)-(−)-1-(4-bromophenyl)ethylamine as a solution in 1.00 L ofdichloromethane. An additional 4 L of dichloromethane was charged to thereactor. The biphasic solution was agitated and cooled to T_(int)=2-3°C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactorin approximately two equal portions ˜6 min apart. It should be notedthat a slight exotherm was noted upon the addition of triphosgene. Theresulting murky solution was agitated at T_(int)=2-5° C. for 30 min, atwhich point HPLC analysis indicates >99 A % conversion (220 nm). Thedichloromethane layer was cut and dried with anhydrous sulfate. Theresulting solution was passed through a celite plug and concentrated to˜1.5 L which fine particles of a white solid developed. The solution wasfiltered and concentrated to a thick oil via reduced pressure to produce239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt %, 79.4%yield). ¹H-NMR spectroscopy (400 MHz, CD₂Cl₂) δ 7.53 (d, J=11.4 Hz, 2H),7.26 (d, J=8.2 Hz, 2H), 4.80 (q, J=6.7 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H).The material was used in Step 3 without further purification.

Step 3.(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one

To a dried 10 L jacketed reactor under a nitrogen atmosphere was charged1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (167 g, 81.7 wt %, 610 mmol,1.00 equiv), 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (219 g, 93.7 wt%, 911 mmol, 1.50 equiv), anhydrous tetrahydrofuran (3.00 L), and then1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 409 mL, 2.73 mol, 4.50 equiv).The resulting solution was agitated and refluxed (T_(int) ⁼67-69° C.,T_(ext)=75° C.) for 19 h, at which point HPLC analysis indicated ˜1 A %(220 nm) of the 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol remained. Thedark solution was cooled to T_(int)=20-25° C. Two liters oftetrahydrofuran were removed by distillation under reduced pressure. Theremaining dark solution was diluted with 4.0 L of ethyl acetate and 1.0L of hexanes. The resulting solution was washed with 4.0 L of a 1.0 Maqueous solution of hydrogen chloride (note: the wash is slightlyexothermic). The aqueous solution was cut and the remaining organicsolution was dried with anhydrous sodium sulfate, filtered and thenconcentrated to an oil via reduced pressure. The resulting material wassubjected to flash silica chromatography (5-30% ethyl acetate/hexanes,1.74 kg of silica) to produce 137.8 g of material (59 wt %, 3.1:1diastereomeric ratio favoring the desired diastereomer(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one,32.3% yield). The material was used in Step 4 without furtherpurification.

Analytical data for(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one:¹H-NMR spectroscopy (500 MHz, CD₂Cl₂) δ 7.42-7.35 (m, 3H), 7.33-7.31 (m,2H), 7.25-7.23 (m, 2H), 6.80-6.74 (m, 2), 5.55 (q, J=7.1 Hz, 1H),5.37-5.36 (m, 1H), 4.89 (s, 1H), 4.69 (s, 1H), 2.96-2.93 (m, 1H), 2.61(dd, J=13.8 and 26.4 Hz, 2H), 2.37-2.25 (m, 3H), 1.68 (s, 3H), 1.50 (d,J=7.1 Hz, 3H). ¹³C-NMR spectroscopy (125 MHz, CD₂Cl₂) δ 152.5, 141.5,140.1, 138.3, 130.6, 128.1, 128.0, 126.9, 124.4, 120.2, 115.3, 82.4,52.1, 50.1, 35.6, 29.8, 23.4, 14.5.

Analytical data for(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one:¹H-NMR spectroscopy (400 MHz, CD₂Cl₂) δ 7.50-7.48 (m, 2H), 7.43-7.39 (m,2H), 7.35-7.32 (m, 3H), 7.20-7.18 (m, 2H), 5.60 (q, J=7.1 Hz, 1H), 4.85(s, 1H), 4.66 (s, 1H), 2.73-2.67 (m, 2H), 2.60 (dd, J=13.9 and 19.4 Hz,2H), 2.28 (dt, J=3.3 and 13.7 Hz, 1H), 2.14-2.05 (m, 1H), 1.66 (s, 3H),1.24 (d, J=7.2 Hz, 3H). ¹³C-NMR spectroscopy (100 MHz, CD₂Cl₂) δ 153.4,142.5, 141.0, 140.1, 131.8, 129.3, 128.9, 127.8, 125.3, 121.5, 116.3,83.9, 53.2, 51.0, 36.6, 31.3, 24.3, 15.4.

Step 4.(6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one

To a 1.0 L 2-neck RBF was charged(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one(135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700mL), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol,2.0 equiv). The resulting solution was agitated at rt (T_(int)=20-25°C.) for 1 h, which HPLC analysis indicates >99 A % (220 nm) conversion.The resulting solution was diluted with 700 mL of methyl tert-butylether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodiumthiosulfate and 1×500 mL of saturated aqueous solution of sodiumbicarbonate. The wash sequence was repeated until the peak on an HPLCtrace of the organic solution that corresponds to a HPLC sample peak ofm-CPBA is <2.5 A % (220 nm), which in this example the wash sequence wasrepeated 3 times. The resulting organic layer was dried with anhydroussodium sulfate, filtered and then concentrated to an oil via reducedpressure. The resulting material was diluted with 200 mL of anhydroustetrahydrofuran and then concentrated to a thick oil via reducedpressure to provide(6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-onewhich was used directly in Step 5.

Step 5.(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

To a 2.0 L 3-neck oven-dried RBF was charged the crude(6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-oneand 750 mL of anhydrous THF. The resulting solution was agitated andcooled to T_(int)=2-3° C. To the agitated clear solution was charged 1.0M lithium triethylborohydride in tetrahydrofuran (Super Hydride, 348 mL,348 mmol, 1.8 equiv). The addition is exothermic and addition wascontrolled to maintain T_(int)=<8° C. The resulting solution wasagitated at T_(int)=2-3° C. for 1.5 h and then allowed to warm toT_(int)=10-13° C. over a 2.5 h, which HPLC analysis indicates ˜94 A %(220 nm) conversion. To the agitated solution was charged a solution ofhydrogen peroxide (95.7 mL of a 35 wt % aqueous solution diluted with400 mL of water, 1.08 mol, 5.60 equiv). The addition is highlyexothermic and addition was controlled to maintain T_(int)=<25° C. Theresulting solution was diluted with 1.00 L of methyl tert-butyl ether(MTBE) and washed with 1.00 L of water followed by 500 mL of a ˜30 wt %solution of sodium thiosulfate. The organic solution was dried withanhydrous sodium sulfate, filtered, and then concentrated via reducedpressure. The resulting material was subjected to flash silicachromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 gof material consisting of both diastereomers (1.98:1 dr) and 41 g of thedesired diastereomer, (>99:1 dr). The material consisting of the mixedfractions was recrystallized from 250 mL of isopropyl acetate (IPAC) and200 mL of heptane (anti-solvent) to produce upon filtration 31.3 g ofproduct (95.7 A % at 220 nm, 74:1 dr). The two samples were combined toproduce 72.3 g of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(83.6% yield for the two step operation). ¹H-NMR spectroscopy (400 MHz,CDCl₃) δ 7.37-7.29 (m, 5H), 7.25-7.21 (m, 2H), 6.82-6.79 (m, 2H), 5.61(q, J=6.9 Hz, 1H), 2.83 (ddd, J=2.5, 5.4 and 11.6 Hz, 1H), 2.39 (ddd,J=5.7, 12.0 and 14.1 Hz, 1H), 2.27 (ddd, J=2.6, 4.8 and 14.0 Hz, 1H),2.21-2.14 (m, 3H), 2.08 (s, 1H), 1.49 (d, J=7.0 Hz, 3H), 1.18 (s, 3H),1.13 (s, 3H). ¹³C-NMR spectroscopy (100 MHz, CDCl₃) δ 153.2, 142.6,138.5, 131.6, 129.13, 129.10, 128.0, 125.3, 121.6, 84.2, 71.4, 54.1,53.3, 36.4, 33.6, 32.1, 30.8, 15.6.

Preparation 2(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(6.6 g, 15.2 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.1 g, 24.3mmol) in dry DMSO (20 mL) was added KOAc (4.8 g, 48.6 mmol) andPd(dppf)cl₂ (372 mg, 0.46 mmol). After addition, the mixture was allowedto warm to 100° C. for 20 h. After TLC showed the starting material haddisappeared, the solid was filtered off. Water (60 mL) and EtOAc (20 mL)were added. The layers were separated and the aqueous layer wasextracted with EtOAc (3×15 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give aresidue, which was purified by column chromatography to give(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(4.4 g, 60%).

(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-onewas prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-onefollowing an analogous procedure.

(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-onewas prepared from(S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

(R)-6-Methoxymethyl-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-onewas prepared from3-[1-(4-bromo-phenyl)-ethyl]-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-onefollowing an analogous procedure.

Preparation 33-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

Preparation of Cobalt(II) Complex

A 50 mL flask was charged withN,N′-bis(3,5-di-tert-butylsalicylidene)-1,1,2,2-tetramethylethenediamine(0.430 g, 0.78 mmol, 1.0 equiv), EtOH (17 mL), and Co(OAc)₂ (0.139 g,0.78 mmol, 1.0 equiv). The mixture was degassed and then heated toreflux under nitrogen for 3 h, cooled to room temperature. Theprecipitate was filtered and the purple solid was washed with EtOH (10mL) and dried under high vacuum to give 0.353 g (75%) of the cobalt(II)complex.

A mixture of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one(490 mg, 1.18 mmol), the cobalt(II) complex whose preparation isdescribed immediately above (8 mg, 0.01 equiv), TsCN (257 mg, 1.2equiv), and PhSiH₃ (137 mg, 157 μL, 1.07 equiv) in ethanol (10 mL) wasstirred 4 h at rt. After removing the solvent under reduced pressure,the residue was purified by chromatography on a 40 g silica gel column,eluted with a 25-80% EtOAc in hexanes gradient to afford3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(267 mg, 51% yield). LC-MS (3 min. method) t_(R)=1.89 min., m/z 441, 443(M+1)

Preparation 42,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile

3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(467 mg, 1.06 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (538 mg, 2equiv), KOAc (333 mg, 3.2 equiv), PdCl₂(dppf)CH₂Cl₂ (27 mg, 0.033 equiv)were mixed with dry DMSO (6 mL). The mixture was degassed and refilledwith N₂ gas 3 times. The mixture was then heated overnight at 90° C.under protection of N₂ gas. After being cooled to rt, the mixture wasdiluted with EtOAc (30 mL), washed with water (20 mL). The aqueous layerwas extracted with EtOAc (2×15 mL). The combined organic layers werewashed by water (15 mL), brine (2×10 mL) and dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified chromatography ona 40 g silica gel column, eluted with a 20-50% EtOAc in Hexanesgradient, to afford2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile(393 mg, 76% yield).

Preparation 53-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrile

Method 1

Step 1. 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol

A 250-mL flask was charged with anhydrous CeCl₃ (5.58 g, 22.6 mmol) andTHF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. Thesuspension was then cooled to −78° C. and a solution of allylmagnesiumbromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one(2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reactionmixture was allowed to slowly warm to 8° C. while stirring overnight (18h). The reaction was then quenched with satd aq NaHCO₃, extracted withEtOAc, and dried over Na₂SO₄. After the solvents were evaporated, theresidue was purified by chromatography on silica gel eluted withhexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol(3.0049 g, 97%) as an oil. LC-MS Method 1 t_(R)=1.79 min, m/z 213, 211(M−OH)⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H),5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H),3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); ¹⁹F NMR (376 MHz, CDCl₃)δ −116.52 (m).

Step 2.(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-oneand(S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (0.413 g, 1.8mmol, 1.0 equiv), (S)-(−)-1-(4-bromophenyl)ethyl isocyanate (0.501 g,2.2 mmol, 1.2 equiv), and DBU (0.738 g, 4.8 mmol, 2.7 equiv) in THF (10mL) was heated to reflux for 25 h. The mixture was diluted with EtOAcand washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc(2×). The combined organic phase was dried over Na₂SO₄. After thesolvents were evaporated, the crude product was directly used in thenext step without further purification.

An analytical sample was purified by chromatography on silica gel elutedwith hexanes/EtOAc to afford the two diastereomers of6-allyl-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.

Isomer 1:(S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.LC-MS Method 1 t_(R)=2.03 min, m/z 420, 418 (MH⁺); ¹H NMR (400 MHz,CDCl₃) δ 7.46 (d, J=8.2 Hz, 2H), 7.31-7.28 (m, 2H), 7.17 (d, J=8.2 Hz,2H), 7.07 (t, J=8.5 Hz, 2H), 5.76-5.66 (m, 2H), 5.10-4.99 (m, 2H),2.75-2.52 (m, 4H), 2.23-2.19 (m, 1H), 2.08-2.00 (m, 1H), 1.24 (d, J=7.0Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −115.07 (m).

Isomer 2:(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.LC-MS Method 1 t_(R)=1.98 min, m/z 420, 418 (MH⁺); ¹H NMR (400 MHz,CDCl₃) δ 7.25-7.20 (m, 4H), 7.05-7.01 (m, 2H), 6.71 (d, J=8.5 Hz, 2H),5.74-5.64 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 5.09-4.99 (m, 2H), 2.92-2.87(m, 1H), 2.63-2.50 (m, 2H), 2.33-2.16 (m, 3H), 1.47 (d, J=7.0 Hz, 3H);¹⁹F NMR (376 MHz, CDCl₃) δ −114.91 (m).

Step 3

A mixture of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(1.067 g, 2.55 mmol, 1.0 equiv), the cobalt(II) catalyst described inPreparation 3 (0.016 g, 0.0264 mmol, 0.010 equiv), TsCN (0.555 g, 3.06mmol, 1.2 equiv), and PhSiH₃ (0.294 g, 2.72 mmol, 1.07 equiv) in EtOH (5mL) was stirred at room temperature for 4 h. After the solvent wasremoved under reduced pressure, the residue was purified bychromatography on silica gel eluted with hexanes/ethyl acetate to afford1.013 g (89%) of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrileas a solid. LC-MS t_(R)=1.83, 1.86 min in 3 min chromatography, m/z 445,447 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.22 (m, 4H), 7.13-7.05 (m,2H), 6.80-6.73 (m, 2H), 5.60-5.56 (m, 1H), 3.00-1.94 (m, 7H), 1.51-1.49(m, 3H), 1.35-1.32 (m, 1.5H), 1.27-1.24 (m, 1.5H); ¹⁹F NMR (376 MHz,CDCl₃) δ −113.08 (m), −113.69 (m).

Step 4

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrile(0.332 g, 0.746 mmol) and MeI (1.40 g, 13 equiv) in THF (12 mL) at −78°C. was added 2.4 mL (2.4 mmol, 3.2 equiv) of a 1.0 M LiHMDS solution inTHF. The resulting mixture was stirred overnight, with the temperatureslowly rising to ambient. The reaction mixture was quenched with brine(1 mL), diluted with CH₂Cl₂, and dried over Na₂SO₄. After the solventswere evaporated, the residue was purified by reversed-phase HPLC(SunFire™ Prep C₁₈ OBD™ 5 μm 19×50 mm column, 10%→90% CH₃CN/H₂O, 0.1%CF₃COOH over 8 min and then 90% CH₃CN/H₂O, 0.1% CF₃COOH over 2 min, flowrate 20 mL/min) to afford 0.2547 g (74%) of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile.LC-MS Method 1 t_(R)=1.89 min, m/z 459, 461 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 7.31-7.27 (m, 2H), 7.22-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.83(d, J=8.2 Hz, 2H), 5.41 (q, J=7.0 Hz, 1H), 3.02-2.97 (m, 1H), 2.42-2.36(m, 1H), 2.29-2.08 (m, 4H), 1.42 (d, J=7.0 Hz, 3H), 1.30 (s, 3H), 1.22(s, 3H); ¹⁹F NMR (376 MHz, CD₃OD) δ −116.50 (m).

Method 2

Step 1

A solution of 3-chloro-1-(4-fluorophenyl)-propan-1-one (18.6 g, 0.1 mol)in THF (50 mL) was added to a well-stirred suspension of zinc power (13g, 0.2 mol) in a mixture of aqueous saturated NH₄Cl solution (260 mL)and THF (65 mL). A solution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2mol) in THF (50 mL) was added dropwise. The reaction mixture was mildlyexothermic, and began to reflux spontaneously. After the refluxing hadceased, the mixture was stirred for 1 h. TLC showed the3-chloro-1-(4-fluorophenyl)propan-1-one not reacted completely. Asolution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL)was added, and the mixture was stirred at rt overnight. The mixture wasextracted with EtOAc (2×500 mL). The combined organic layer was driedand concentrated. The residue was purified by column chromatography onsilica gel eluted with petroleum ether/EtOAc 50:1→430:1→5:1, to give1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76%) asan oil.

Step 2

A mixture of 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (3.15 g,13 mmol), (S)-(−)-1-(-bromophenyl)ethyl isocyanate (3.5 g, 16 mmol), andDBU (8 g, 33 mmol) in THF (80 mL) was heated to reflux for 25 h. Themixture was diluted with EtOAc and washed with 1N aq HCl. The aqueousphase was extracted with EtOAc (3×). The combined organic phase wasdried over Na₂SO₄. After the solvents were evaporated, the crude productwas purified by column to give(R)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(4-fluorophenyl)-6-(2-methylallyl)-1,3-oxazinan-2-one(2.13 g, yield: 38%).

Step 3

A mixture of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-methylallyl)-1,3-oxazinan-2-one(2.13 g, 4.9 mmol), the cobalt(II) catalyst described in Preparation 3(0.032 g, 0.053 mmol), TsCN (1.11 g, 6.12 mmol), and PhSiH₃ (0.6 g, 5.54mmol) in EtOH (10 mL) was stirred at room temperature for 8 h. After thesolvent was removed under reduced pressure, the residue was purified bycolumn chromatography to give3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(1.84 g, 81.1%).

Preparation 63-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(730 mg, 1.59 mmol) in DMSO (8 mL) was added bis(pinacolato)diboron (480mg, 1.89 mmol), KOAc (480 mg, 4.89 mmol) and Pd(dppf)Cl₂ (45 mg, 0.042mmol) under nitrogen atmosphere. The formed mixture was stirred at 90°C. for 20 h. The reaction was quenched with water and extracted withEtOAc. The combined organic phase was dried over anhydrous Na₂SO₄ andconcentrated to give the crude product, which was purified by columnchromatography to give3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile(191 mg, 23.7%).

Preparation 7(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

A mixture of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(0.4910 g, 1.17 mmol, 1.0 equiv), bis(pinacolato)diboron (0.3925 g, 1.55mmol, 1.3 equiv), KOAc (0.3696 g, 3.76 mmol, 3.2 equiv), andPdCl₂(dppf).CH₂Cl₂ (0.0316 g, 0.0386 mmol, 0.033 equiv) in DMSO (6 mL)was heated at 90° C. under N₂ for 20 h. After cooling, the reactionmixture was partitioned between EtOAc and water. The organic phase waswashed with brine, and dried over Na₂SO₄. After the solvents wereevaporated, the residue was purified by chromatography on silica geleluted with hexanes/ethyl acetate to give 0.4776 g (87%) of(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneas a white solid.

Preparation 8

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(5 g, 12.5 mmol) in tetrahydrofuran (60 mL) was added BH₃ THF (25 mL, 1mol/L, 25 mmol) at 0° C. under nitrogen atmosphere. The formed mixturewas stirred for 2 h. The reaction was quenched with water. Then NaOH (3mol/L, 10 mL) and H₂O₂ (15 mL) were added to the above mixture. When thereaction was over, the mixture was extracted with EtOAc. The combinedorganic phase was concentrated to give the crude product, which waspurified by column chromatography to give(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(2.5 g, 40%). ¹H NMR: (400 MHz, CDCl₃): δ=1.48 (t, 3H), 1.53 (m, 1H),1.73 (m, 1H), 1.93-1.98 (m, 2H), 2.17-2.28 (m, 3H), 3.57 (t, 2H), 5.59(m, 1H), 6.72 (m, 2H), 7.20 (m, 2H), 7.25-7.37 (m, 5H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-onewas prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-onefollowing an analogous procedure.

(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

Preparation 9(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

To a solution of((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(2 g, 4.8 mmol) in DMSO (30 mL) were added bis(pinacolato)diboron (1.58g, 6.3 mmol), KOAc (1.51 g, 15.4 mmol) and PdCl₂ (130 mg, 0.16 mmol)under nitrogen atmosphere. The formed mixture was stirred at 90° C. for20 h. The reaction was quenched with water and extracted with EtOAc. Thecombined organic phase was concentrated to give the crude product, whichwas purified by column chromatography to give(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(1.7 g, 77%). ¹H NMR: (400 MHz, CDCl₃): δ=1.18 (t, 1H), 1.33 (S, 11H),1.43 (m, 2H), 1.48 (m, 3H), 1.71 (m, 1H), 1.88 (m, 2H), 2.1-2.3 (t, 3H),2.7 (m, 1H), 3.5 (m, 2H), 5.5 (m, 1H), 6.72 (m, 2H), 7.25-7.37 (m, 5H),7.48 (m, 2H).

(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-onefollowing an analogous procedure.

(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

Preparation 10(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(methoxymethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1. 1-Methoxy-2-phenyl-pent-4-en-2-ol

2-Methoxy-1-phenyl-ethanone (5.00 g) dissolved in tetrahydrofuran (50mL) was added to 2 M allylmagnesium chloride in tetrahydrofuran (21 mL)at room temperature. The solution was stirred at room temperature for 3h and then 10% aqueous NH₄Cl solution (50 mL) was added. The resultingmixture was extracted with tert-butyl methyl ether (3×50 mL) and thecombined extracts were washed with water (50 mL) and brine (50 mL). Thesolvent was evaporated to afford the title compound as a colorless oil.Yield: 6.40 g (quantitative). Mass spectrum (ESI⁺): m/z=175 [M+H−H₂O]⁺

Step 2. 5-Methoxy-4-phenyl-pentane-1,2,4-triol

OsO₄ (4% in water, 2 mL; alternatively, K₂OsO₄ may be used) followed byN-methyl-morpholine-N-oxide (5.20 g) was added to a solution of1-methoxy-2-phenyl-pent-4-en-2-ol (1.10 g) in tetrahydrofuran (10 mL)chilled in an ice bath. The cooling bath was removed and the solutionwas stirred at room temperature overnight. Then, 10% aqueous Na₂S₂O₅solution (10 mL) was added and the resulting mixture was stirred at roomtemperature for another 1.5 h. After removal of the organic solventunder reduced pressure, the remaining mixture was extracted with ethylacetate. The combined extracts were washed with brine and dried (MgSO₄).The solvent was evaporated to afford the title compound in good purity(ca. 95%). Yield: 1.20 g (96% of theory). Mass spectrum (ESI⁻): m/z=225[M−H]⁻

Step 3. 3-Hydroxy-4-methoxy-3-phenyl-butyraldehyde

NalO₄ (5.20 g) was added to a mixture of5-methoxy-4-phenyl-pentane-1,2,4-triol (1.10 g), dichloromethane (10mL), and water (5 mL) chilled in an ice bath. The mixture was stirredvigorously while warming to ambient temperature in the cooling bath andfurther stirred at this temperature overnight. Then, water (20 mL) anddichloromethane (50 mL) were added, the organic layer was separated, andthe aqueous layer was extracted with dichloromethane (2×25 mL). Thecombined organic phases were washed with water and dried (MgSO₄). Afterremoval of the solvent, the title compound was yielded which wasdirectly submitted to the next reaction step (glycol cleavage).

Yield: 0.94 g (quantitative)

Step 4.4-[(S)-1-(4-Bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-ol

(S)-1-(4-Bromo-phenyl)-ethylamine (0.93 g), NaB(OAc)₃ (0.98 g), andacetic acid (0.27 mL) were added in the given order to a solution of3-hydroxy-4-methoxy-3-phenyl-butyraldehyde (0.90 g) in tetrahydrofuran(20 mL) at ca. 10-15° C. The cooling bath was removed and the mixturewas stirred at room temperature for 2 h. Then, water (50 mL) and 1 Maqueous NaOH solution (20 mL) were added and the resulting mixture wasstirred for another 30 min. The mixture was extracted with ethyl acetateand the combined extracts were washed with water and brine. After drying(MgSO₄), the solvent was removed to give the title compound which wassubmitted to the subsequent reaction step without further purification.Yield: 1.80 g (quantitative). Mass spectrum (ESI⁺): m/z=378/380 (Br)[M+H]⁺

Step 5.3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-oneand3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-one

Triphosgene (157 mg) was added to an ice-cold solution of4-[(S)-1-(4-bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-ol (1:1diastereomeric mixture, 200 mg) and EtNiPr₂ (91 μL) in dichloromethane(5 mL). The resulting solution was stirred with cooling for 2 h and atroom temperature overnight. Then, the solution was concentrated underreduced pressure and the residue was purified by HPLC on reversed phase(MeCN/H₂O/NH₃) to afford the title compounds in separate fractions.

Isomer 1:3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-one.Yield: 45 mg (21% of theory). Mass spectrum (ESI⁺): m/z=404 [M+H]⁺ ¹HNMR (400 MHz, DMSO-d₆) δ 1.41 (d, J=7.1 Hz, 3H), 2.19 (td, J=11.2, 5.2Hz, 1H), 2.24-2.34 (m, 1H), 2.34-2.41 (m, 1H), 3.02-3.09 (m, 1H), 3.27(s, 3H), 3.49 (d, B part of an AB signal, J=10.6 Hz, 1H), 3.53 (d, Apart of an AB signal, J=10.6 Hz, 1H), 5.34 (q, J=7.0 Hz, 1H), 6.80 (dm,J=8.4 Hz, 2H), 7.27 (dm, J=8.4 Hz, 2H), 7.32-7.42 (m, 5H).

Isomer 2:3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl-6-phenyl-[1,3]oxazinan-2-one.Yield: 45 mg (21% of theory). Mass spectrum (ESI⁺): m/z=404 [M+H]⁺ ¹HNMR (400 MHz, DMSO-d₆) δ 1.20 (d, J=7.2 Hz, 3H), 2.13-2.23 (m, 1H),2.32-2.40 (m, 1H), 2.63-2.72 (m, 1H), 2.73-2.81 (m, 1H), 3.26 (s, 3H),3.48 (d, B part of an AB signal, J=10.6 Hz, 1H), 3.55 (d, A part of anAB signal, J=10.6 Hz, 1H), 5.35 (q, J=7.2 Hz, 1H), 7.19 (dm, J=8.4 Hz,2H), 7.32-7.45 (m, 5H), 7.53 (dm, J=8.4 Hz, 2H).

Preparation 11N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamide

Step 1

To a solution of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(200 mg, 0.48 mmol) in CH₂Cl₂ (5 mL) was added Et₃N (240 mg, 2.4 mmol)and methanesulfonyl chloride (164 mg, 1.4 mmol) at 0° C. The reactionsolution was stirred at rt for 1 h. The reaction was quenched with H₂Oand the mixture was extracted with CH₂Cl₂. The organic phase wasconcentrated to give3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propylmethanesulfonate (234 mg, 98%), which was used for the next step withoutfurther purification.

Step 2

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propylmethanesulfonate (234 mg, 0.24 mmol) in CH₂Cl₂ (3 mL) was added NaH (82mg, 3.4 mmol) at 0° C. The mixture was stirred at rt for 30 min. ThenN-methylacetamide (204 mg, 2.8 mmol) was added the above mixture. Theformed mixture was stirred at 80° C. for 5 h. After the reaction wasover, the reaction was quenched with water and the mixture was extractedwith EtOAc. The combined organic phase was concentrated to give thecrude product, which was purified by preparative TLC to giveN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamide(150 mg, 68%). LC-MS Method 2 tR=1.50 min, m/z=497, 495, 475, 473. ¹HNMR (400 MHz, CDCl₃): δ=1.41 (m, 1H), 1.48 (t, 3H), 1.73 (m, 1H),1.83-1.95 (m, 2H), 2.01 (m, 3H), 2.1-2.3 (m, 3H), 2.71 (m, 1H), 2.81 (s,3H), 3.1 (m, 1H), 3.2 (m, 1H), 5.5 (m, 1H), 6.72 (m, 2H), 7.10 (m, 2H),7.20 (m, 2H), 7.37 (m, 3H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure using pyrrolidin-2-one in Step 2.

Preparation 12(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(3 g, 7.5 mmol) in CH₂Cl₂ (50 mL) was treated with O₃ at −78° C. tillthe mixture turned blue. Then NaBH₄ (285 mg, 75 mmol) was added to thesolution at 0° C., and the reaction solution was stirred at roomtemperature for 3 hours. The reaction was quenched by H₂O, and themixture was extracted with EtOAc. The combined organic phase wasconcentrated to give the crude product, which was purified bypreparative TLC to give(S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one(2.5 g, 84%). ¹H NMR (CDCl₃): 1.48 (t, 3H), 2.05-2.41 (m, 4H), 2.71-2.92(m, 2H), 3.51 (m, 1H), 3.71 (m, 1H), 5.58 (m, 1H), 6.73 (d, 2H), 7.12(m, 2H), 7.23-7.45 (m, 6H).

Preparation 13(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one(300 mg, 0.75 mmol) in dichloromethane (20 mL) were added Et₃N (390 mg,3.75 mmol) and methanesulfonyl chloride (256 mg, 2.25 mmol) at 0° C. Thereaction solution was stirred at rt for 1 h. The reaction was quenchedwith H₂O and the mixture was extracted with dichloromethane. The organicphase was concentrated to give2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl-methanesulfonate (352.8 mg, 98%), which was used for the next step withoutfurther purification.

Step 2

To a solution of2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl-methanesulfonate(360 mg, 0.75 mmol) and K₂CO₃ (207 mg, 1.5 mmol) in acetonitrile (10 mL)was added isothiazolidine 1,1-dioxide (121 mg, 4.6 mmol), and themixture was refluxed overnight. The mixture was filtered and thefiltrate was concentrated to give the crude product, which was purifiedby preparative HPLC to afford compound(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one(2.43 mg, 1%). LC-MS Method 2 t_(R)=1.37 min, m/z=509, 507. ¹H NMR(CDCl₃): 1.48 (t, 3H), 2.05-2.41 (m, 7H), 2.71-2.92 (m, 2H), 3.11 (m,3H), 3.21 (m, 2H), 5.58 (m, 1H), 6.73 (d, 2H), 7.18 (m, 1H), 7.23 (m,3H); 7.35 (m, 3H).

(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(1,1-dioxo-isothiazolidin-2-yl)propyl)-6-phenyl-1,3-oxazinan-2-onewas prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-onefollowing an analogous procedure.

Preparation 14(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one

Step 1

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(450 mg, 1.01 mmol) in acetone (10 mL) was added a solution of KMnO₄(190 mg, 1.2 mmol) and NalO₄ (1.5 g, 7.2 mmol) in water (10 mL). Themixture was stirred for 2 h at 0° C. The mixture was filtered and thefiltrate was adjusted to pH 5-6 with aqueous 1 N aq HCl solution. Themixture was extracted with EtOAc. The organic phase washed with brine,dried over anhydrous Na₂SO₄ and concentrated to give2-((S)-3-((S)-1-(4-bromophen-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)aceticacid (540 mg, crude), which was used for the next step withoutpurification.

Step 2

To a solution of2-((S)-3-((S)-1-(4-bromophen-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)aceticacid (540 mg, 1.24 mol) in MeOH (20 mL) was added SOCl₂ (5 mL) at 0° C.,and the reaction mixture was stirred at rt for 2 h. The reaction mixturewas concentrated and the residue was purified by preparative TLC to givemethyl2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate(150 mg, 27%). ¹H NMR (CDCl₃): δ=1.49 (d, 3H), 2.19 (m, 1H), 2.44 (m,1H), 2.60 (m, 1H), 2.77-3.08 (m, 3H), 3.51 (s, 3H), 5.52 (m, 2H), 6.62(d, 2H), 6.98 (t, 2H), 7.23 (t, 2H), 7.28 (m, 2H).

Step 3

To a solution of methyl2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate(150 mg, 0.33 mmol), and tetraisopropoxytitanium (189 mg, 0.66 mmol) inTHF (20 mL) was added 3.0 M ethylmagnesium bromide (4 mL, 12 mmol) at rtunder nitrogen. Then the mixture was stirred for 2 h. The reaction wasquenched with aqueous NH₄Cl solution, and the mixture was filtered. Thefiltrate was extracted with EtOAc. The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated to give thecrude product, which was purified by preparative HPLC to give(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one(2.51 mg, 2%). ¹H NMR (CDCl₃): 0.03 (m, 1H), 0.18 (m, 1H), 0.49 (m, 1H),0.60 (m, 1H), 1.43 (m, 3H), 2.08 (s, 2H), 2.26 (m, 1H), 2.37 (m, 2H),2.88 (m, 1H), 5.53 (m, 1H), 6.66 (d, 2H), 6.97 (t, 2H), 7.16 (m, 2H),7.26 (m, 2H).

Preparation 15N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylmethanesulfonamide

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl methanesulfonate (180 mg, 0.36 mmol) in DMF (5 mL) was added NaH(14.6 mg, 0.36 mmol) at 0° C. The mixture was stirred at rt for 30 min.Then iodomethane (153 mg, 1.1 mmol) was added to the above mixture. Theformed mixture was stirred at 40° C. for 3 h. After the reaction wasover, the reaction was quenched with NH₄Cl solution and the mixture wasextracted with EtOAc. The combined organic phase was concentrated togive the crude product, which was purified by preparative TLC to giveN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylmethanesulfonamide(100 mg, 55%). LC-MS Method 2 t_(R)=1.41 min, m/z=511, 509. ¹H NMR (400MHz, CDCl₃): δ=1.45 (m, 1H), 1.48 (t, 3H), 1.83-1.97 (m, 3H), 2.1-2.2(m, 3H), 2.61 (s, 3H), 2.71 (s, 3H), 2.91 (m, 1H), 3.0 (m, 2H), 5.5 (m,1H), 6.72 (m, 2H), 7.10 (m, 2H), 7.20 (m, 2H), 7.37 (m, 3H).

EXAMPLE 16-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2-methylnicotinonitrile

Step 1

To a solution of 6-amino-2-methyl-nicotinonitrile (1 g, 7.5 mmol) inaqueous HBr solution (48%, 1.25 g, 7.5 mmol) was added bromine (2.4 g,15 mmol) at 0° C. A solution of NaNO₂ (1.3 g, 19 mmol) in water (5 mL)was added dropwise. The mixture was warmed to rt and stirred for 1.5 h.The solution was poured into iced water (20 mL). The aqueous mixture wasneutralized with NaOH (1N, 5 mL), and extracted with EtOAc (4×10 mL).The combined organic layers were dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel to give a white solid (500 mg, 34%).

Step 2

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-(S-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-ethyl)-1,3-oxazinan-2-one(400 mg, 0.84 mmol) and 6-bromo-2-methylnicotinonitrile (164 mg, 0.84mmol) in dry 1,4-dioxane (5 mL) was added Cs₂CO₃ (1 mL, 2M) andPd(PPh₃)₂Cl₂ (40 mg). The mixture was heated at 110° C. for 2 h. AfterTLC showed the starting material had disappeared, the solid was filteredoff. Water (5 mL) and EtOAc (5 mL) were added, the aqueous layer wasextracted with EtOAc (3×8 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered, and concentrated. After HPLCpurification,6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2-methylnicotinonitrilewas obtained (100 mg, 26%). LC-MS Method 2 t_(R)=1.363 min, m/z=412; ¹HNMR (CDCl₃): δ1.02 (s, 3H), 1.14 (s, 3H), 1.51 (d, 3H), 2.10-2.22 (m,4H), 2.30-2.40 (m, 1H), 2.73 (s, 3H), 2.85 (m, 1H), 3.53 (m, 2H),3.60-3.80 (m, 2H), 5.65 (m, 1H), 7.01 (d, 2H), 7.15-7.32 (m, 5H), 7.50(d, 1H), 7.70 (d, 2H), 7.80 (d, 1H).

EXAMPLE 26-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-cyclopropylnicotinamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-(S-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-ethyl)-1,3-oxazinan-2-oneand 6-bromo-N-cyclopropylnicotinamide following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.223 min,m/z=523.3; ¹H NMR (CDCl₃) 0.66-0.71 (m, 2H), 0.93 (m, 2H), 1.24 (s, 3H),1.47 (s, 3H), 1.57 (m, 3H), 2.19 (s, 2H), 2.23-2.34 (m, 2H), 2.48 (m,2H), 2.92 (m, 2H), 5.67 (m, 1H), 6.36 (d, 1H), 6.97 (d, 2H), 7.34-7.40(m, 5H), 7.72 (m, 3H), 8.18 (m, 1H), 8.97 (s, 1H)

EXAMPLE 3N-tert-butyl-6-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 6-bromo-N-tert-butylnicotinamide following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.323 min,m/z=539.3; ¹H NMR (CDCl₃) 1.35 (s, 3H), 1.49 (s, 3H), 1.53 (s, 9H), 1.56(m, 3H), 2.18 (m, 2H), 2.33 (m, 1H), 2.49 (m, 2H), 2.93 (m, 1H), 5.70(m, 1H), 6.00 (m, 1H), 6.98 (d, 2H), 7.38 (m, 5H), 7.34-7.40 (m, 5H),7.69-7.74 (m, 3H), 8.13 (m, 1H), 9.00 (s, 1H)

EXAMPLE 4(S)-3-((S)-1-(4-(6-cyclopropylpyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

A mixture of ethyl 3-iodopropanoate (8 g, 35 mmol) and zinc-copper (4.5g, 70 mmol) in a mixture of benzene (80 mL) and DMA (8 mL) was heated at60° C. for 4.5 hours under N₂. Pd(PPh₃)₂Cl₂ (1.2 g, 1.8 mmol) was added,followed by addition of cyclopropanecarbonyl chloride (3.7 g, 35 mmol).The mixture was stirred at 60° C. for another 30 minutes. The reactionmixture was diluted with ethyl acetate (300 mL), and washed with 1N HCl(50 mL), satd aq NaHCO₃ (80 mL) and brine (30 mL). The organic layer wasdried over Na₂SO₄ and concentrated to afford the ethyl4-cyclopropyl-4-oxobutanoate (4.2 g), which was used for next stepdirectly without purification.

Step 2

A mixture of ethyl 4-cyclopropyl-4-oxobutanoate (2.2 g, 13 mmol, crude)and N₂H₄.H₂O (3.3 mL, 85%, 56 mmol) in EtOH (20 mL) was refluxed for 4h. The mixture was concentrated, and the residue was treated with amixture of ethyl acetate (100 mL) and water (20 mL). The organic layerwas dried over Na₂SO₄ and concentrated to give the crude product, whichwas purified by preparative TLC to give6-cyclopropyl-4,5-dihydropyridazin-3-ol (200 mg, 11%). ¹H NMR (400 MHz,CD₃OD): δ0.79 (m, 4H), 1.62 (m, 1H), 2.26 (m, 4H).

Step 3

To a solution of 6-cyclopropyl-4,5-dihydropyridazin-3-ol (200 mg, 1.5mmol) in AcOH (6 mL) was added Br₂ (695 mg, 4.4 mmol) at 70° C. Themixture was stirred at 70° C. for 15 minutes, and more Br₂ (695 mg, 4.4mmol) was added. The mixture was refluxed for 2 hours, and concentrated.The residue was diluted with ethyl acetate (60 mL), the organic layerwas washed with satd aq NaHCO₃ solution (20 mL). The organic layer wasdried over Na₂SO₄ and concentrated to give6-cyclopropyl-4,5-dihydropyridazin-3-ol (182 mg, 91%). ¹H NMR (400 MHz,CD₃OD): δ0.75 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 6.79 (d, 2H), 7.25(d, 1H).

Step 4

A mixture of 6-cyclopropylpyridazin-3-ol (182 mg, 1.3 mmol) in POCl₃ (15mL) was refluxed for 1 hour, and concentrated. The residue was treatedwith ethyl acetate (60 mL) and sat. NaHCO₃ aqueous solution (10 mL) at0° C. The organic layer was dried over Na₂SO₄ and concentrated to afford3-chloro-6-cyclopropylpyridazine (185 mg, 89%). ¹H NMR (400 MHz, CD₃OD):δ1.11 (m, 2H), 1.20 (m, 2H), 2.25 (m, 1H), 7.52 (d, 1H), 7.67 (d, 1H).

Step 5

A mixture ofS-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one(868 mg, 1.8 mmol), 3-chloro-6-cyclopropylpyridazine (350 mg, 2.26mmol), PdCl₂(PPh₃)₂ (509 mg, 0.7 mmol) and 2 M aq Cs₂CO₃ solution (4.6mL) in 1,4-dioxane (9 mL) was heated to reflux for 2 h. The reactionmixture was concentrated. The residue was treated with water (60 mL),and extracted with ethyl acetate (360 mL×3). The combined organic phasewas dried over Na₂SO₄ and concentrated to give the crude product, whichwas purified by preparative TLC and preparative HPLC to afford(S)-3-((S)-1-(4-(6-cyclopropylpyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(104.5 mg, 12%). LC-MS Method 2 t_(R)=1.068 min, m/z=472.3; ¹H NMR (400MHz, CD₃OD): δ1.06 (s, 3H), 1.08 (m, 2H), 1.13 (s, 3H), 1.19 (m, 2H),1.50 (d, 3H), 2.10 (m, 1H), 2.12 (s, 2H), 2.20 (m, 2H), 2.30 (m, 1H),2.78 (m, 1H), 5.65 (m, 1H), 6.96 (d, 2H), 7.25 (m, 6H), 7.55 (d, 1H),7.74 (d, 2H).

EXAMPLE 5(S)-3-((S)-1-(4-(5-chloro-6-methylpyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-oneand(S)-3-((S)-1-(4-(6-chloro-3-methylpyridazin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The isomeric title compounds were prepared by reaction of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4,6-dichloro-3-methylpyridazine following a procedure analogous tothat described in Example 14.

Isomer 1: LC-MS Method 1 t_(R)=1.6 min, m/z=480, 482 (M+1); ¹H NMR(CD₃OD) 8.19 (s, 1H), 7.85 (d, 2H), 7.35 (m, 5H), 7.13 (d, 2H), 5.61 (q,1H), 3.08 (m, 1H), 2.79 (s, 3H), 2.48 (m, 3H), 2.26 (td, 1H), 2.15 (s,2H), 1.58 (d, 3H), 1.26 (s, 3H), 0.95 (s, 3H).

Isomer 2: LC-MS Method 1 t_(R)=1.53 min, m/z=480, 482 (M+1); ¹H NMR(CD₃OD) 7.58 (s, 1H), 7.35 (m, 4H), 7.31-7.22 (m, 3H), 7.13 (d, 2H),3.11 (m, 1H), 2.53 (s, 3H), 2.23 (td, 1H), 2.16 (s, 2H), 1.57 (d, 3H),1.27 (s, 3H), 0.96 (s, 3H).

4,6-dichloro-3-methylpyridazine was prepared following the proceduredescribed in WO 2003/041712 (Intermediate A3, p 12).

EXAMPLE 6(S)-3-((S)-1-(4-(6-tert-butylpyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-bromo-6-tert-butylpyridazine following a procedure analogous tothat described in Example Step 2. 3-bromo-6-tert-butylpyridazine wasprepared from pivaloyl chloride following procedures analogous to thosedescribed in Example 4 Steps 1-4 using POBr₃ in place of POCl₃ in Step4. LC-MS Method 2 t_(R)=1.208 min, m/z=488.3; ¹H NMR (CD₃OD) 0.94 (s,3H), 1.25 (s, 3H), 1.48 (s, 9H), 1.57 (d, 3H), 2.15 (s, 2H), 2.29 (m,1H), 2.50 (m, 2H), 3.10 (m, 1H), 5.60 (m, 1H), 7.14 (d, 2H), 7.30 (m,5H), 7.81 (d, 2H), 8.07 (d, 1H), 8.20 (d, 1H)

EXAMPLE 7(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-(2-hydroxypropan-2-yl)pyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a stirred solution of 3-chloro-6-methylpyridazine (12.8 g, 100 mol)in concentrated H₂SO₄ (100 mL) was added powered K₂Cr₂O₇ (35.3 g, 120mmol) slowly at 50° C. The reaction mixture was stirred at 50° C. for 4h, and poured into the iced water carefully. The mixture was extractedwith EtOAc. The combined organic layer was washed with brine, dried overNa₂SO₄, and filtered. The solvent was removed under vacuum to afford the6-chloropyridazine-3-carboxylic acid (9.25 g, 59%), which was useddirectly in the next step. ¹H NMR (DMSO-d₆, 400 MHz): δ8.21 (d, J=4.8Hz, 1H), 8.06 (d, J=4.8 Hz, 1H).

Step 2

To a stirred solution of 6-chloropyridazine-3-carboxylic acid (12.5 g,0.078 mol) in CH₂Cl₂ (80 mL) at 0° C. were added triphosgene (11.6 g,0.039 mol), Et₃N (55 mL, 0.4 mol), and N,O-dimethylhydroxylaminehydrochloride (7.6 g, 0.078 mol). The reaction mixture was stirred atroom temperature for 2 h. The salt was filtered, after removal of thesolvent in vacuo, the residue was purified by column chromatography toafford 6-chloro-N-methoxy-N-methylpyridazine-3-carboxamide (13.5 g,86%). ¹H NMR (DMSO-d₆, 400 MHz): δ 8.08 (d, J=9.2 Hz, 1H), 8.06 (d,J=9.2 Hz, 1H), 3.33 (s, 3H), 8.06 (s, 3H).

Step 3

To a solution of 6-chloro-N-methoxy-N-methylpyridazine-3-carboxamide(13.5 g, 0.0659 mol) in THF (600 mL) was added CH₃MgBr (43.2 ml, 0.13mol) at −78° C. under N₂. The reaction mixture was stirred at −78° C.for 2 h, quenched by addition of aq NH₄Cl and filtered. The filtrate wasextracted with EtOAc. The combined organic layer was washed with brine,dried over Na₂SO₄, and filtered. The solvent was removed under vacuum,and the residue was purified by column chromatography to afford1-(6-chloropyridazin-3-yl)ethanone. (9.3 g, 90% yield). ¹H NMR (CDCl₃,400 MHz): δ 8.03 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 2.81 (s,3H).

Step 4

To a solution of 1-(6-chloropyridazin-3-yl)ethanone (120 mg, 0.757 mol)in THF (5 mL) was added MeMgBr (0.38 mL, 1.14 mol), and stirred at −78°C. for 30 min and at rt for 30 minutes. The reaction mixture wasquenched with satd aq NH₄Cl, and extracted with EtOAc. The combinedorganic layer was dried over Na₂SO₄ and concentrated to give an oil,which was purified by prep TLC to give the product (1:2 PE/EtOAcA). ¹HNMR (CD₃OD): δ1.61 (s, 6H), 3.30 (m, 1H), 7.76 (d, 1H), 8.00 (d, 2H).

Step 5

A solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(50 mg, 0.104 mmol), 2-(6-chloropyridazin-3-yl)-propan-2-ol (20 mg,0.151 mmol), Pd(PPh₃)₂Cl₂ (30 mg, 0.046 mmol), 2 M aq Cs₂CO₃ (0.4 mL) indioxane (5 mL) was heated at reflux for 2 h. The reaction mixture wasconcentrated, and the residue was treated with water (20 mL) andextracted with EtOAc (3×10 mL). The combined organic layer was washedwith satd aq NaCl solution, dried with anhydrous Na₂SO₄, andconcentrated to give an oil, which was purified by preparative TLC andHPLC to give the product. LC-MS Method 2 t_(R)=1.031 min, m/z=490.3; ¹HNMR (CD₃OD): δ0.89 (s, 1H), 0.96 (s, 3H), 1.28 (m, 6H), 1.57 (d, 3H),1.66 (m, 6H), 2.15 (s, 2H), 2.28 (m, 1H), 2.56 (m, 2H), 3.08 (m, 1H),5.62 (m, 1H), 7.13 (d, 2H), 7.38 (m, 5H), 7.82 (m, 2H), 8.05 (m, 2H).

EXAMPLE 8N-tert-butyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridazine-3-carboxamide

Step 1

To a solution of methyl 6-chloropyridazine-3-carboxylate (36 mg, 0.2mmol) in DME (6 mL) was added Pd(PPh₃)₄ (20 mg, 0.02 mmol) under N₂. Themixture was stirred at room temperature for 1 h.(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one(96 mg, 0.2 mmol) in EtOH (2 mL) and satd aq NaHCO₃ (2 mL) were added.The mixture was stirred at 100° C. for another 2 h under N₂. Thereaction mixture was quenched by addition of H₂O, and extracted byEtOAc. The combined organic phase was dried and concentrated to give thecrude product, which was purified by preparative TLC to give6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-pyridazine-3-carboxylicacid (63 mg, 60%).

Step 2

To a solution of6-(4-(S-1-(S-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridazine-3-carboxylicacid (479 mg, 1.0 mmol) in CH₂Cl₂ (50 mL) was added DIEA (2 mL, 10mmol), HOBt (675 mg, 5 mmol), EDCl (985 mg, 5 mmol), and2-methylpropan-2-amine (438 mg, 6 mmol) at 0° C. under N₂. The mixturewas stirred at rt overnight. The reaction was quenched by addition ofHCl (1 N), and extracted with CH₂Cl₂. The combined organic phase wasdried over Na₂SO₄ and concentrated to give the crude product, which waspurified by preparative TLC to giveN-tert-butyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-pyridazine-3-carboxamide(230 mg, 51%). LC-MS Method 2 t_(R)=1.372 min, m/z=473.1; ¹H NMR(CDCl₃): δ1.07 (s, 3H), 1.12 (s, 3H), 1.48 (m, 9H), 1.52 (d, 3H), 2.04(m, 1H), 2.20 (s, 2H), 2.22 (m, 2H), 2.36 (m, 1H), 2.87 (m, 1H), 5.68(m, 1H), 7.08 (m, 2H), 7.20-7.30 (m, 5H), 7.8 (m, 2H), 8.09 (m, 1H),8.25 (m, 1H).

EXAMPLE 9N-tert-butyl-6-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridazine-3-carboxamide

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand methyl 6-chloropyridazine-3-carboxylate following proceduresanalogous to those described in Example 8. LC-MS Method 2 t_(R)=1.404min, m/z=540.3; ¹H NMR (CDCl₃) 1.33 (s, 3H), 1.46 (s, 3H), 1.51 (s, 9H),1.59 (m, 3H), 2.13 (m, 2H), 2.36 (m, 1H), 2.51 (m, 2H), 2.95 (m, 1H),5.70 (m, 1H), 6.99 (m, 2H), 7.38 (m, 5H), 7.83 (m, 2H), 7.92 (m, 1H),8.16 (m, 1H), 8.32 (m, 1H)

EXAMPLE 10N-cyclopropyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridazine-3-carboxamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-oneand methyl 6-chloropyridazine-3-carboxylate following proceduresanalogous to those described in Example 8 using cyclopropylamine in Step2. LC-MS Method 2 t_(R)=1.221 min, m/z=457.1; ¹H NMR (CDCl₃) 0.67 (m,2H), 0.88 (m, 2H), 1.20 (s, 3H), 1.23 (s, 3H), 1.54 (d, 3H), 2.20 (m,4H), 2.3 (s, 1H), 2.9 (m, 1H), 3.0 (m, 2H), 5.7 (m, 1H), 7.0 (m, 2H),7.28-7.34 (m, 5H), 7.8 (m, 2H), 7.90 (m, 1H), 8.2 (m, 1H), 8.3 (m, 1H)

EXAMPLE 116-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-cyclopropylpyridazine-3-carboxamide

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand methyl 6-chloropyridazine-3-carboxylate following proceduresanalogous to those described in Example 8 using cyclopropylamine in Step2. LC-MS Method 2 t_(R)=1.17 min, m/z=524.3; ¹H NMR (CDCl₃) 0.71 (m,2H), 0.94 (m, 2H), 1.34 (s, 3H), 1.48 (s, 3H), 1.59 (m, 3H), 2.18 (m,2H), 2.36 (m, 1H), 2.53 (m, 2H), 2.94 (m, 1H), 3.02 (m, 1H), 5.72 (m,1H), 7.03 (m, 2H), 7.39 (m, 5H), 7.84 (m, 2H), 7.93 (m, 1H), 7.25 (m,1H), 8.34 (m, 1H)

EXAMPLE 12(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(11.37 g, 28.5 mmol) in tetrahydrofuran (250 mL) was added BH₃ THF (80mL, 1 mol/L, 4 mmol) at 0° C. under nitrogen atmosphere. The mixture wasstirred for 2 h, quenched by addition of water. NaOH solution (3 mol/L,16 mL) and H₂O₂ (45 mL) were added to the above mixture. When reactionwas over, the mixture was extracted with EtOAc. The combined organiclayer was concentrated to give the crude product, which was purified bycolumn chromatography to give(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(4.32 g, 36.4%). ¹H NMR: (400 MHz, CDCl₃): δ1.48 (t, 3H), 1.53 (m, 1H),1.73 (m, 1H), 1.93-1.98 (m, 2H), 2.17-2.28 (m, 3H), 3.57 (t, 2H), 5.59(m, 1H), 6.72 (m, 2H), 7.20 (m, 2H), 7.25-7.37 (m, 5H).

Step 2

(R)-3-(S-1-(4-bromophenyl)-ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one(500 mg, 1.2 mmol) was dissolved in 20 mL of acetone, and cooled in anice bath. The mixture was added Jones reagent (0.7 mL, 1.8 mmol) slowly,and stirred for 1 h. Solvents were removed in vacuum, and the residuewas dissolved in a mixture of dichloromethane (30 mL) and water (30 mL).The aqueous layer was extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over Na₂SO₄, andconcentrated to give the crude product, which was purified bypreparative TLC to give the3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoicacid (300 mg, 60%).

Step 3

To a solution of3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoicacid (1 g, 2.23 mmol) in CH₂Cl₂ (10 mL) was added SOCl₂ (1.37 g, 11.5mmol) at 0° C. The mixture was heated to reflux for 2 h. The solvent wasremoved to afford3-(R-3-(S-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-propanoylchloride (0.85 g, 82%).

To a mixture of3-(R-3-(S-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-propanoylchloride (0.85 g, 1.9 mmol) and acetohydrazide (0.74 g, 10 mmol) inCH₂Cl₂ (5 mL) was added Et₃N (1.01 g, 10 mmol) at 0° C. The mixture wasstirred at 0° C. for 1 h and washed with satd aq NaHCO₃. The organiclayer was dried over Na₂SO₄ and concentrated to affordN′-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazide(0.9 g, 97%).

Step 4

To a solution ofN′-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazide(0.1 g, 0.21 mmol) in THF (2 mL) was added Burgess Reagent (75 mg, 0.315mmol). The sealed vial was irradiated in the microwave at 100° C. for 15min. The mixture was extracted with EtOAc (3×30 mL). The combinedorganic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by preparative TLCto afford(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one(58 mg, yield: 59%). ¹H NMR (CDCl₃): δ1.49-1.51 (m, 3H), 2.23-2.26 (m,2H), 2.30-2.33 (m, 2H), 2.42 (s, 3H), 2.43-2.45 (m, 1H), 2.49-2.54 (m,1H), 2.87-2.91 (m, 1H), 3.06-3.09 (m, 1H), 5.61-5.63 (m, 1H), 6.76-6.78(d, 2H), 7.20-7.22 (m, 2H), 7.26-7.33 (m, 2H), 7.35-7.37 (m, 3H).

Step 5

To a solution of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one(490 mg, 1.04 mmol), and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (424 mg,1.67 mmol) in dry DMSO (20 mL) was added KOAc (326 mg, 3.33 mmol) andPd(dppf)Cl₂ (25.3 mg, 0.031 mmol) under N₂ atmosphere. The mixture waswarmed at 100° C. for 3 h. After TLC showed the starting material haddisappeared, the solid was filtered off, water (50 mL) and EtOAc (50 mL)were added, and the mixture was extracted with EtOAc (3×50 mL). Thecombined organic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by prep TLC toafford(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(0.395 g, yield: 73.6%).

Step 6

(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-chloro-6-methylpyridazine were reacted following a procedureanalogous to that described in Example 1 Step 2 to afford(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one.LC-MS Method 2 t_(R)=0.984 min, m/z=499.1; ¹H NMR (CD₃OD) 1.50 (m, 3H),2.25 (m, 2H), 2.42 (m, 1H), 2.35 (s, 3H), 2.38 (m, 1H), 2.42 (m, 1H),2.49-2.55 (m, 1H), 2.65 (s, 3H), 2.90 (m, 1H), 3.05 (m, 1H), 5.52 (m,1H), 7.07 (m, 2H), 7.25 (m, 3H), 7.32 (m, 2H), 7.69-7.76 (m, 3H), 8.06(m, 1H)

EXAMPLE 13(S)-3-((S)-1-(4-(5-fluoropyrimidin-2-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-oneand 2-chloro-5-fluoropyrimidine a procedure analogous to that describedin Example 1 Step 2. LC-MS Method 2 t_(R)=1.327 min, m/z=391.9; ¹H NMR(CDCl₃) 1.11 (s, 3H), 1.18 (s, 3H), 1.52 (d, 3H), 2.20 (m, 4H), 2.38 (m,1H), 2.85 (m, 1H), 5.72 (m, 1H), 7.08 (m, 2H), 7.20-7.40 (m, 5H), 8.12(m, 2H), 8.61 (m, 2H)

EXAMPLE 14(S)-3-((S)-1-(4-(2-(1H-imidazol-1-yl)pyrimidin-5-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

A microwave vial equipped with a flea stir bar was charged with(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one(20 mg, 0.042 mmol), 5-bromo-2-(1H-imidazol-1-yl)pyrimidine (19 mg,0.083 mmol), Cs₂CO₃ (27 mg, 0.083 mmol), water (0.1 mL) and dioxane (1mL). The mixture was sparge with N₂ for 10 min and PdCl₂(dppf) (2 mg,0.003 mmol) was added. The mixture was sparged with N₂ for 10 min andheated at 110° C. for 10 min in the microwave. The mixture was dilutedwith MeOH (1 mL), filtered and the filtrate was purified directly byprep HPLC to afford the title compound (12.1 mg, 58%) as an oil. LC-MSMethod 1 t_(R)=1.27 min, m/z=498; ¹H NMR (CD₃OD) 0.96 (s, 3H), 1.27 (s,3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.26 (m, 1H), 2.50 (2H), 3.12 (m, 1H),5.60 (q, 1H), 7.18 (d, 2H), 7.25-7.40 (5H), 7.58 (d, 2H), 7.77 (s, 1H),8.47 (s, 1H), 9.12 (s, 2H), 9.88 (s, 1H)

EXAMPLE 15N-cyclopropyl-5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-oneand 5-bromo-N-cyclopropylpyrimidine-2-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.167 min, m/z=515.2; ¹H NMR (CDCl₃) 0.65 (m, 2H), 0.87 (m, 2H),1.09 (m, 6H), 1.51 (m, 3H), 2.26 (m, 2H), 2.31 (m, 2H), 2.43 (m, 3H),2.83 (m, 1H), 2.98 (m, 1H), 5.67 (m, 1H), 7.06 (m, 1H), 7.25 (m, 7H),8.02 (m, 1H), 8.89 (m, 2H)

EXAMPLE 165-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-cyclopropylpyrimidine-2-carboxamide

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 5-bromo-N-cyclopropylpyrimidine-2-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.237 min, m/z=524.3; ¹H NMR (CDCl₃) 0.62 (m, 2H), 0.83 (m, 2H),1.32 (s, 3H), 1.44 (s, 3H), 1.49 (d, 3H), 2.08 (m, 2H), 2.24 (m, 1H),2.42 (m, 2H), 2.90 (m, 2H), 5.61 (m, 1H), 6.93 (m, 2H), 7.20-7.36 (m,7H), 8.00 (s, 1H), 8.88 (s, 2H).

EXAMPLE 17N-tert-butyl-5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-oneand 5-bromo-N-tert-butylpyrimidine-2-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.287 min, m/z=531.3; ¹H NMR (CDCl₃) 1.11 (s, 3H), 1.18 (s, 3H),1.49 (s, 9H), 1.54 (m, 3H), 2.04 (s, 1H), 2.11 (m, 2H), 2.21 (m, 2H),2.34 (m, 1H), 2.78 (m, 1H), 5.67 (m, 1H), 7.06 (m, 2H), 7.19 (m, 1H),7.25 (m, 6H), 7.84 (s, 1H), 8.85 (s, 2H).

EXAMPLE 18(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(2-methylpyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromo-2-methylpyrimidine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.035 min,m/z=484.1; ¹H NMR (CD₃OD) 1.57 (m, 3H), 2.29 (m, 2H), 2.38 (m, 1H), 2.41(s, 3H), 2.47 (m, 1H), 2.50 (m, 1H), 2.63 (m, 1H), 2.72 (s, 3H), 2.96(m, 1H), 3.15 (m, 1H), 5.58 (m, 1H), 7.12 (m, 2H), 7.33 (m, 3H), 7.38(m, 2H), 7.47 (m, 2H), 8.88 (s, 2H).

EXAMPLE 19N-cyclopropyl-2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)thiazole-4-carboxamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-N-cyclopropylthiazole-4-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.252 min, m/z=542.1; ¹H NMR (CDCl₃) 0.61 (m, 2H), 0.81 (m, 2H),1.04 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.06-2.24 (m, 5H), 2.29-2.40(m, 1H), 2.71-2.89 (m, 2H), 5.62 (m, 1H), 6.94-7.01 (m, 2H), 7.19-7.31(m, 5H), 7.35 (s, 1H), 7.61 (m, 2H), 8.01 (s, 1H).

EXAMPLE 20N-cyclopropyl-2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)thiazole-5-carboxamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-N-cyclopropylthiazole-5-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.219 min, m/z=462.1; ¹H NMR (CDCl₃) 0.51 (m, 2H), 0.81 (m, 2H),1.04 (s, 3H), 1.12 (s, 3H), 1.47 (d, 3H), 2.06-2.24 (m, 5H), 2.29-2.40(m, 1H), 2.71-2.89 (m, 2H), 5.62 (m, 1H), 6.09 (s, 1H), 6.94 (m, 2H),7.21-7.39 (m, 5H), 7.61 (m, 2H), 8.01 (s, 1H)

EXAMPLE 212-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-cyclopropylthiazole-5-carboxamide

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 2-bromo-N-cyclopropylthiazole-5-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.262 min, m/z=529.3; ¹H NMR (CDCl₃) 0.63 (m, 2H), 0.86 (m, 2H),1.30 (s, 3H), 1.43 (s, 3H), 1.52 (d, 3H), 2.02 (s, 2H), 2.29 (m, 1H),2.81-2.99 (m, 2H), 5.62 (m, 1H), 6.50 (s, 1H), 6.89 (d, 2H), 7.37 (m,5H), 7.60 (m, 2H), 8.14 (s, 1H)

EXAMPLE 22N-tert-butyl-2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)thiazole-4-carboxamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-N-tert-butylthiazole-4-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.315 min, m/z=478.3; ¹H NMR (CDCl₃) 1.18 (s, 3H), 1.36 (s, 3H),1.49 (s, 9H), 2.11 (d, 3H), 2.14 (s, 4H), 2.33 (m, 1H), 2.80 (m, 1H),5.64 (m, 1H), 7.19 (m, 2H), 7.28-7.39 (m, 5H), 7.60 (m, 2H), 7.94 (s,1H)

EXAMPLE 23N-tert-butyl-2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)thiazole-5-carboxamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-N-tert-butylthiazole-5-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.351 min, m/z=558.1; ¹H NMR (CDCl₃) 1.13 (s, 3H), 1.16 (s, 3H),1.49 (s, 9H), 1.51 (d, 3H), 2.15-2.32 (m, 5H), 2.41 (m, 1H), 2.89 (m,1H), 3.72 (m, 1H), 5.70 (m, 1H), 5.78 (m, 1H), 7.02 (m, 2H), 7.34 (m,5H), 7.70 (m, 2H), 8.08 (m, 1H)

EXAMPLE 24N-tert-butyl-2-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)thiazole-5-carboxamide

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 2-bromo-N-tert-butylthiazole-5-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.292 min, m/z=545.4; ¹H NMR (CDCl₃) 1.25 (s, 3H), 1.40 (s, 3H),1.49 (d, 3H), 2.11 (s, 2H), 2.26 (m, 1H), 2.42 (m, 2H), 2.88 (m, 1H),5.61 (m, 1H), 5.73 (s, 1H), 6.85 (m, 2H), 7.31 (m, 5H), 7.60 (m, 2H),8.00 (m, 1H).

EXAMPLE 25N-tert-butyl-3-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-1-methyl-1H-pyrazole-5-carboxamideandN-tert-butyl-5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-1-methyl-1H-pyrazole-3-carboxamide

Step 1

Sodium (23 g, 1 mol) was dissolved in a mixture of dry EtOH (250 mL) anddry Et₂O (200 mL) under nitrogen. The mixture was cooled to 0° C. in aniced water bath. Diethyl oxalate (73 g, 0.5 mol) was dissolved in Et₂O(25 mL) was added dropwise, the reaction mixture was stirred for 30 min,a solution of CH₃CN (20.5 g, 0.5 mol) in Et₂O (25 mL) was added, and themixture was stirred for 1 h. The solid was collected by filtration togive sodium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (90 g) which wasused without purification.

Step 2

To a suspension of sodium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate(1.44 g, 8.78 mmol) in CHCl₃ (80 mL) was added HCl (5 mL) in ethylether. t-butyl hydrazinecarboxylate (1.16 g, 8.78 mmol) was added, themixture was stirred for 24 h at rt, the precipitate was removed byfiltration, and the filtrate was concentrated to give 1-tert-butyl5-ethyl 3-amino-1H-pyrazole-1,5-dicarboxylate (1.2 g, 37%), which waspurified by preparative TLC. ¹H NMR: δ 1.34 (m, 3H), 1.66 (s, 9H), 4.36(m, 2H), 5.84 (s, 1H),

Step 3

To a solution of t-butyl 5-ethyl 3-amino-1H-pyrazole-1,5-dicarboxylate(1.1 g, 3.0 mmol) in conc HCl solution (18 mL) was added a solution ofNaNO₂ (414 mg, 6.0 mmol) in water (2 mL) over 3 min at 0° C. A solutionof KI (1.26 g, 7.5 mmol) in water (3 mL) was added to the reactionmixture over 5 min, resulting in nitrogen evolution. The reactionmixture was stirred for 5 min. Water was added, the aqueous mixture wasextracted with EA, washed with NaS₂O₃ (2×), dried over Na₂SO₄, andconcentrated to give ethyl 3-iodo-1H-pyrazole-5-carboxylate (600 mg,75%), which was purified by preparative TLC. ¹H NMR: δ 1.31 (m, 3H),4.32 (m, 2H), 6.90 (s, 1H).

Step 4

To a solution of ethyl 3-iodo-1H-pyrazole-5-carboxylate (600 mg, 2.56mmol) and K₂CO₃ (609 mg, 4.51 mmol) in dry CH₃CN (10 mL) was added MeI(974 mg, 6.77 mmol). The mixture was stirred at room temperatureovernight under N₂. After TLC showed that starting material haddisappeared, the solid was filtered. Solvent was removed and the residuewas purified to give methyl 3-iodo-1-methyl-1H-pyrazole-5-carboxylateand methyl 5-iodo-1-methyl-1H-pyrazole-3-carboxylate.

Isomer 1: ¹H NMR: δ 1.29 (m, 3H), 4.10 (s, 3H), 4.29 (m, 2H), 6.88 (s,1H).

Isomer 2:

Step 5

To a solution of isomer 1 of the product from Step 4 (200 mg, 0.71 mmol)and(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(285 mg, 0.60 mmol) in dry dioxane (6 mL) was added Cs₂CO₃ (0.6 mL, 1.2mmol) and Pd(PPh₃)₂Cl₂ (30 mg). After addition, the mixture was stirredat 110° C. for 2 h under nitrogen. After TLC showed the startingmaterial had disappeared, the solid was filtered off. Water (20 mL) andEtOAc (20 mL) were added, the aqueous layer was extracted with EtOAc(3×10 mL). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated to give methyl3-(4-(S-1-(S-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-methyl-pyrazole-5-carboxylateisomer 1 (280 mg, 92%), which was purified by preparative TLC. ¹H NMR(CDCl₃): δ1.09 (s, 3H), 1.18 (s, 3H), 1.36 (m, 3H), 1.50 (d, 3H), 2.19(m, 6H), 2.34 (m, 1H), 2.80 (m, 1H), 4.19 (s, 3H), 4.33 (m, 2H), 5.66(m, 1H), 7.31 (m, 6H), 7.52 (m, 3H).

Step 6

To a solution of methyl3-(4-(S-1-(S-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-methyl-pyrazole-5-carboxylateisomer 1 (280 mg, 0.55 mmol) in dry MeOH (6 mL) was added LiOH (1.10mmol) at 0° C. The mixture was stirred at rt overnight. After TLC showedthe stating material had disappeared, MeOH was removed in vacuo. 1N aqHCl and EtOAc were added to adjust the pH=6˜7, the aqueous layer wasextracted with EtOAc (3×15 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered, and concentrated to give3-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-methyl-pyrazole-5-carboxylicacid isomer 1 (200 mg, 74%), which was purified by preparative TLC.

Step 7

A mixture of3-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-methyl-pyrazole-5-carboxylicacid isomer 1 (100 mg, 0.21 mmol), 2-methylpropan-2-amine (31 mg, 0.42mmol), EDCl (83 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol), and DIEA (1 mL)in dry CH₂Cl₂ (6 mL) at 0° C. was stirred at it overnight undernitrogen. After TLC showed the starting material had disappeared, thesolvent was removed in vacuo to giveN-tert-butyl-3-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-methyl-pyrazole-5-carboxamideisomer 1 (21 mg, 19%), which was purified by preparative HPLC. LC-MSMethod 2 t_(R)=1.35 min, m/z=475.3; ¹H NMR (CDCl₃): δ 1.09 (s, 3H), 1.18(s, 3H), 1.43 (s, 9H), 1.52 (d, 3H), 2.22 (m, 4H), 2.38 (m, 1H), 2.87(m, 1H), 4.16 (s, 3H), 5.68 (m, 1H), 5.82 (s, 1H), 6.60 (s, 1H), 6.99(d, 2H), 7.27-7.40 (m, 5H), 7.50 (d, 2H).

N-tert-butyl-3-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-methyl-pyrazole-5-carboxamideisomer 2 was prepared from isomer 2 of the product of Step 4 followingprocedures analogous to those described in Step 5-7. LC-MS Method 2t_(R)=1.335 min, m/z=475.3; 1H NMR (CDCl3) 1.12 (s, 3H), 1.19 (s, 3H),1.48 (s, 9H), 1.54 (d, 3H), 2.12 (m, 1H), 2.18-2.39 (m, 4H), 2.53 (m,1H), 2.91 (m, 1H), 3.80 (s, 3H), 5.71 (m, 1H), 6.70 (s, 1H), 6.76 (m,1H), 7.02 (d, 2H), 7.13 (m, 2H), 7.30 (m, 1H), 7.34 (m, 4H)

EXAMPLE 26(S)-3-((S)-1-(4-(2-(2,4-dimethyl-1H-imidazol-1-yl)pyrimidin-5-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromo-2-(2,4-dimethyl-1H-imidazol-1-yl)-pyrimidine following aprocedure analogous to that described in Example 1 Step 2. LC-MS Method2 t_(R)=0.962 min, m/z=526.3; ¹H NMR (CD₃OD) 0.86 (s, 3H), 1.16 (s, 3H),1.49 (m, 3H), 2.06 (m, 2H), 2.12 (m, 1H), 2.20 (s, 3H), 2.35-2.48 (m,2H), 2.82 (s, 3H), 3.03 (m, 1H), 5.53 (m, 1H), 7.07 (m, 2H), 7.19-7.32(m, 6H), 7.45 (m, 2H), 7.80 (m, 1H), 8.96 (s, 2H).

To a solution of 5-bromo-2-chloropyrimidine (0.3 g, 1.55 mmol) in NMP(15 mL) were added 2,4-dimethyl-1H-imidazole (0.224 g, 2.2 mmol) andK₂CO₃ (0.43 g, 3.1 mmol). The resulting solution was stirred at 80° C.overnight. After water (50 mL) and EtOAc (50 mL) were added, the mixturewas extracted with EtOAc (3×50 mL). The combined organic layer waswashed with brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by pre-TLC to afford5-bromo-2-(2,4-dimethyl-1H-imidazol-1-yl)-pyrimidine (0.2 g, 51%).

EXAMPLE 27(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-(2-methyl-1H-imidazol-1-yl)pyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromo-2-(2-methyl-1H-imidazol-1-yl)-pyrimidine following aprocedure analogous to that described in Example 1 Step 2. LC-MS Method2 t_(R)=0.932 min, m/z=512.3; ¹H NMR (CD₃OD) 0.86 (s, 3H), 1.16 (s, 3H),1.49 (m, 3H), 2.15 (m, 2H), 2.18 (m, 1H), 2.37-2.49 (m, 2H), 2.79 (s,3H), 3.03 (m, 1H), 5.53 (m, 1H), 7.01-7.06 (m, 3H), 7.21-7.29 (m, 5H),7.44 (m, 2H), 7.97 (m, 1H), 8.95 (s, 2H).

5-bromo-2-(2-methyl-1H-imidazol-1-yl)-pyrimidine was prepared5-bromo-2-chloropyrimidine and 2-methylimidazole following a procedureanalogous to that described for5-bromo-2-(2,4-dimethyl-1H-imidazol-1-yl)-pyrimidine in Example 26.

EXAMPLE 28(S)-3-((S)-1-(4-(6-(cyclopentyloxy)pyridin-2-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-oneand2-(cyclopentyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinefollowing a procedure analogous to that described in Example 14. LC-MSMethod 1 t_(R)=2.23 min, m/z=515, 457; ¹H NMR (CD₃OD) 0.96 (s, 3H), 1.27(s, 3H), 1.56 (d, 3H), 1.70 (2H), 1.85 (4H), 2.05 (2H), 2.17 (s, 2H),2.24 (m, 1H), 2.46 (2H), 3.05 (m, 1H), 5.47 (m, 1H), 5.58 (q, 1H), 6.70(d, 1H), 7.00 (d, 2H), 7.25-7.40 (6H), 7.70 (t, 1H), 7.77 (d, 2H).

EXAMPLE 29(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of 5-bromo-2-chloropyrimidine (600 mg, 3.13 mmol) in dryDMF (10 mL) under N₂ were added tributyl(1-ethoxyvinyl)stannane (1.09mL, 3.23 mmol) and Pd(PPh₃)₂Cl₂ (113 mg, 0.161 mmol). The mixture wasstirred at 100° C. for 3 h and at rt for 16 h. The mixture was dilutedwith ether (20 mL), and treated with aqueous KF solution (5 g of KF in 3mL of water). The mixture was stirred vigorously for 1 h at roomtemperature before being filtered through diatomaceous earth. Thefiltrate was washed with satd aq NaHCO₃ and brine. The aqueous phase wasextracted with EtOAc. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated to give2-chloro-5-(1-ethoxyvinyl)pyrimidine (350 mg, yield 61%).

Step 2

To a solution of 2-chloro-5-(1-ethoxyvinyl)pyrimidine (350 mg, 1.9 mmol)in THF (15 mL) was, added aqueous HCl (1N, 15 mL). The mixture wasstirred at rt for 4 h, extracted with EtOAc. The organic phase waswashed with satd aq NaHCO₃ and brine. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated to give the crude product,which was purified by prep TLC (PE:EA 3:1) to give1-(2-chloropyrimidin-5-yl)ethanone (268 mg, yield 90%).

Step 3

To a solution of 1-(2-chloropyrimidin-5-yl)ethanone (268 mg, 1.7 mmol)in THF (20 mL) was added MeMgBr (2.68 mL, 8.04 mmol) at −78° C. undernitrogen. The solution was stirred at −78° C. for 20 min, quenched withsatd aq NH₄Cl, and extracted with EtOAc. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated to give an oil, which waspurified by prep TLC (PE:EA 3:1) to give2-(2-chloropyrimidin-5-yl)propan-2-ol (150 mg, yield 51%).

Step 4

To a solution of 2-(2-chloropyrimidin-5-yl)propan-2-ol (30 mg, 0.17mmol) in DME (6 mL) was added Pd(PPh₃)₄ (10 mg, 0.01 mmol) undernitrogen. The mixture was stirred at room temperature for 1 hour.(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(60 mg, 0.125 mmol) in EtOH (2 mL) was added, followed by addition ofsatd aq NaHCO₃ (2 mL). The mixture was stirred at 100° C. for 2 h. Thereaction was quenched with water, and extracted with EtOAc. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated to give(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(21 mg, yield 25%). LC-MS Method 2 t_(R)=0.98 min, m/z=512, 490, 472,432; ¹H NMR (CD₃OD): δ 1.02 (s, 3H), 1.13 (s, 3H), 1.50 (d, 3H), 1.61(s, 6H), 2.02 (s, 1H), 2.18 (m, 5H), 2.30 (m, 1H), 2.75 (m, 1H), 5.66(m, 1H), 7.00 (m, 2H), 7.20-7.33 (m, 5H), 8.10 (m, 2H), 8.92 (s, 2H).

EXAMPLE 30(S)-3-((S)-1-(4-(6-(dimethylamino)pyridin-2-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-6-(dimethylamino)pyridine following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.39 min, m/z=474; ¹HNMR (CD₃OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.58 (d, 3H), 2.18 (s, 2H), 2.28(m, 1H), 2.50 (2H), 3.12 (m, 1H), 3.34 (s, 6H), 5.59 (q, 1H), 6.99 (d,1H), 7.18 (3H), 7.25-7.40 (5H), 7.57 (d, 2H), 7.98 (m, 1H).

EXAMPLE 31(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of sodium cyanide (168.35 mg, 3.36 mmol),triethylenediamine (60 mg, 0.52 mmol) in a mixture of DMSO (0.7 mL) andwater (1.4 mL) was added a solution of 5-bromo-2-chloropyrimidine (500mg, 2.59 mmol) in DMSO (1.3 mL). The solution was stirred at rtovernight, diluted with water, and extracted with EtOAc. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated to give5-bromopyrimidine-2-carbonitrile (500 mg, yield 100%, crude).

Step 2

To a solution of 5-bromopyrimidine-2-carbonitrile (300 mg, 1.63 mmol) inTHF (20 mL) was added MeMgBr (5.43 mL, 16.3 mmol) at −78° C. undernitrogen. The solution was stirred at −78° C. for 20 min., quenched withsatd aq NH₄Cl, and extracted with EtOAc. The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated to give an oil, which waspurified by prep TLC (3:1 PE/EtOAc) to give1-(5-bromopyrimidin-2-yl)ethanone (99 mg, yield 30.2%). ¹H NMR (CDCl₃):δ2.70 (s, 3H), 8.90 (m, 2H).

Step 3

To a solution of 1-(5-bromopyrimidin-2-yl)ethanone (99 mg, 0.50 mmol) inTHF (10 mL) was added MeMgBr (1.65 mL, 4.95 mmol) at −78° C. undernitrogen. The formed solution was stirred at −78° C. for 20 min,quenched with satd aq NH₄Cl, and extracted with EtOAc. The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated to givean oil, which was purified by prep TLC (3:1 PE/EtOAc) to give2-(5-bromopyrimidin-2-yl)propan-2-ol (50 mg, yield: 46.77%).

Step 4

To a solution of 2-(5-bromopyrimidin-2-yl)propan-2-ol (30 mg, 0.14 mmol)in DME (6 mL) was added Pd(PPh₃)₄ (10 mg, 0.01 mmol) under nitrogen. Themixture was stirred at room temperature for 1 h.(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(60 mg, 0.125 mmol) in EtOH (2 mL) was added, followed by addition ofsatd aq NaHCO₃ (2 mL). The mixture was stirred at 100° C. for 2 h,quenched with water, and extracted with EtOAc. The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated to give(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one(17 mg, yield 25.12%). LC-MS Method 2 t_(R)=1.00 min, m/z=490; ¹H NMR(CD₃OD): δ0.95 (s, 3H), 1.27 (s, 3H), 1.57 (d, 3H), 1.61 (s, 6H), 2.22(s, 2H), 2.25 (m, 1H), 2.50 (m, 2H), 3.06 (m, 1H), 5.61 (m, 1H), 7.10(m, 2H), 7.34 (m, 5H), 7.45 (m, 2H), 8.92 (s, 2H).

EXAMPLE 32 4108.1002-007 Example 206-methyl-6-phenyl-3-(3-(pyridin-3-yl)phenyl)-1,3-oxazinan-2-one

The title compound was prepared from3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and3-pyridylboronic acid following procedures analogous to those in Example1 Step 2. LC-MS Method 2, t_(R)=1.819 min, m/z=345.1. ¹H NMR (CDCl₃)1.80 (s, 3H), 2.45-2.65 (m, 2H), 3.40 (m, 1H), 3.62 (m, 1H), 7.30-7.60(m, 8H), 7.85 (m, 1H), 8.40 (m, 1H), 8.75 (m, 1H), 9.00 (m, 1H),9.30-9.50 (b, 2H).

EXAMPLE 33 4108.1002-007 Example 336-methyl-6-phenyl-3-(3-(pyridin-4-yl)phenyl)-1,3-oxazinan-2-one

The title compound was prepared from3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and4-pyridylboronic acid following procedures analogous to those in Example1 Step 2. LC-MS Method 2, t_(R)=1.329 min, m/z=345.1. ¹H NMR (CDCl₃)1.70 (s, 3H), 2.30-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 4.10 (m,2H), 7.27-7.50 (m, 9H), 8.60 (b, 1H).

EXAMPLE 34 4108.1002-007 Example 205(S)-6-(2-hydroxyethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand pyridine-3-boronic acid using a procedure analogous to thatdescribed in Example 1 Step 2 followed by treatment with (i) ozone and(ii) NaBH₄. LC-MS Method 2 t_(R)=1.44, min, m/z=403; ¹H NMR (CDCl₃) 1.50(t, 3H), 1.68 (m, 2H), 1.91 (m, 2H), 2.05 (m, 1H), 2.26 (m, 2H), 2.83(m, 1H), 3.53 (m, 2H), 5.62 (q, 1H), 6.93 (d, 2H), 7.20-7.32 (m, 8H),7.73 (m, 1H), 8.51 (s, 1H), 8.72 (s, 1H).

EXAMPLE 35 4108.1002-007 Example 210(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand pyridine-4-boronic acid using a procedure analogous to thatdescribed in Example 1 Step 2 followed by a procedure analogous to thatdescribed in Example 12 Step 1. LC-MS Method 2 t_(R)=2.2, min, m/z=417;¹H NMR (CDCl₃) 1.48 (m, 2H), 1.50 (t, 2H), 1.92 (m, 2H), 2.28 (m, 3H),2.89 (m, 1H), 3.53 (m, 3H), 5.66 (m, 1H), 6.99 (m, 2H), 7.28 (q, 8H),7.52 (d, 2H), 8.51 (m, 1H), 8.63 (m, 1H).

EXAMPLE 36 4108.1002-007 Example 211(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand pyridine-3-boronic acid using a procedure analogous to thatdescribed in Example 1 Step 2 followed by a procedure analogous to thatdescribed in Example 12 Step 1. LC-MS Method 2 t_(R)=1.5, min, m/z=417;¹H NMR (CDCl₃) 1.32 (m, 2H), 1.50 (t, 3H), 1.68 (m, 2H), 1.91 (m, 2H),2.15 (m, 1H), 2.26 (m, 2H), 2.83 (m, 1H), 3.51 (m, 2H), 5.62 (q, 1H),6.93 (d, 2H), 7.20-7.32 (m, 8H), 7.73 (m, 1H), 8.51 (s, 1H), 8.72 (s,1H).

EXAMPLE 37 4108.1002-007 Example 214(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-oneand pyridine-3-boronic acid using a procedure analogous to thatdescribed in Example 1 Step 2 followed by treatment with (i) ozone and(ii) NaBH₄. LC-MS Method 2 t_(R)=1.412, min, m/z=421.2; ¹H NMR (CDCl₃)1.52 (d, 3H), 2.03-2.17 (m, 3H), 2.22-2.32 (m, 3H), 2.81 (m, 1H),3.47-3.52 (m, 1H), 3.72 (m, 1H), 5.63 (m, 1H), 6.93-7.01 (m, 4H),7.21-7.26 (m, 2H), 7.28-7.33 (m, 3H), 7.73 (m, 1H), 8.51 (m, 1H), 8.68(m, 1H).

EXAMPLE 38 4108.1002-007 Example 2223-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine1-oxide

A mixture of(R)-1-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)tetra-hydropyrimidin-2(1H)-one(30 mg, 0.07 mmol) and 3-chloro-perbenzoic acid (84 mg, 0.49 mmol) inTHF (1.5 mL) was stirred at rt for 3 h. Satd aq NaHCO₃ was added to thereaction mixture, and the organic layer was separated. The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated to give thecrude product, which was purified by preparative HPLC to give3-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine1-oxide (2.83 mg, 9%). LC-MS Method 2 t_(R)=1.623, min, m/z=433.2; ¹HNMR (400 MHz, CDCl₃): δ=1.54 (t, 3H), 1.94 (m, 2H), 2.21-2.24 (m, 2H),2.35-2.39 (m, 2H), 2.49 (m, 1H), 3.1 (m, 1H), 3.44 (m, 1H), 5.57 (m,1H), 7.07 (m, 2H), 7.28-7.42 (m, 6H), 7.58 (m, 1H), 7.77 (m, 1H), 8.19(m, 1H), 8.28 (m, 1H), 8.49 (m, 1H).

EXAMPLE 39 4108.1002-007 Example 230(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

To a 16 mm culture tube with a Teflon-coated stirring bar, a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(87 mg, 0.209 mmol) in dry DMSO (4 mL) and dry methanol (1.5 mL),triethylamine (60 μL, 2 equiv), Pd(OAc)₂ (10 mg, 0.2 equiv) and1,3-bis(diphenylphosphino)propane (35 mg, 0.4 equiv) were added. Thetube was sealed with a septum and Parafilm tape. The reaction mixturewas purged with CO gas through a long needle for 1 min. A balloon filledwith CO gas was attached to maintain a CO atmosphere. The reactionmixture was submerged in an oil bath preheated to 85° C. and stirredvigorously. After 12 h, LC-MS showed the reaction was complete. Themixture was filtered through a thin pad of Celite. The Celite was washedwith EtOAc (35 mL). The filtrate was washed with 3% aq HCl (10 mL),water (2×8 mL) and brine (2×7 mL), and dried over Na₂SO₄. Afterfiltration and concentration, the residue was purified by chromatographyon a 12-g silica gel cartridge eluted with a 10-60% EtOAc in hexanesgradient to afford methyl4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate(68.4 mg, 83%). LC-MS Method 1, t_(R)=1.79 min, m/z=398. ¹H NMR (CDCl₃)7.79 (d, 2H), 7.26 (m, 2H), 7.04 (t, 2H), 6.94 (d, 2H), 5.69 (m, m, 2H),5.07 (dd, 2H), 3.89 (s, 3H), 2.94 (m, 1H), 2.58 (m, 2H), 1.54 (d, 3H).

Step 2

methyl4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoatewas treated with LiOH to afford4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoicacid.

Step 3

4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoicacid (40 mg, 0.104 mmol) was dissolved in CH₂Cl₂ (6 mL). At 0° C.,thionyl chloride (1 mL, excess) was added slowly. After 10 min., themixture was warmed up to rt and stirred 1 h at rt The mixture wasconcentrated and redissolved in CH₂Cl₂ (6 mL). NaHCO₃ (22 mg, 2.5equiv.) and acetohydrazide (12 mg, 1.5 equiv.) were added slowly. Afterstirring 1 h at rt, LC-MS found reaction completed. The mixture wasdiluted with CH₂Cl₂ (10 mL), filtered NaHCO₃ and washed by water (5 mL),5% aq HCl (2×5 mL), satd aq NaHCO₃ (4 mL), brine (4 mL) and dried overNa₂SO₄. After filtration and concentration, the crudeN′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide(34 mg, 74%) was used for next step without further purification.

Step 4

N′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide(4 mg, 0.009 mmol) was dissolved in 5:1 toluene/pyridine (1.5 mL).Phosphorus pentasulfide (8.1 mg, 2 equiv.) was added and the mixture washeated in Microwave Oven for 25 min at 130° C. LC-MS found reactioncompleted. The mixture was diluted with EtOAc (8 mL), washed with 5% HCl(2×5 mL), satd aq NaHCO₃ solution (4 mL), brine (4 mL) and dried overNa₂SO₄. After filtration and concentration, the residue was purified byprep HPLC to afford 2.43 mg (61% yield). LC-MS Method 1 t_(R)=1.7, min,m/z=438; ¹H NMR (CDCl₃) 7.66 (d, 2H), 7.26 (t, 2H), 7.02 (t, 2H), 6.97(d, 2H), 5.69 (m, 2H), 5.07 (dd, 2H), 2.98 (m, 1H), 2.83 (s, 3H), 1.56(d, 3H).

EXAMPLE 40 4108.1002-007 Example 235(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand 2-methoxypyridine-5-boronic acid using a procedure analogous to thatdescribed in Example 1 Step 2 followed by a procedure analogous to thatdescribed in Example 12 Step 1. LC-MS Method 3 t_(R)=1.22, min, m/z=447;¹H NMR (CDCl₃) 1.01 (d, 1H), 1.10 (d, 1H), 1.49 (s, 3H), 1.85-1.95 (m,1H), 2.00-2.07 (m, 1H), 2.21-2.30 (m, 2H), 2.40 (m, 1H), 2.35 (m, 1H),3.87 (m, 1H), 3.90 (s, 3H), 3.95 (m, 1H), 5.61 (m, 1H), 6.71 (d, 1H),6.83 (d, 1H), 6.91 (m, 1H), 7.16 (m, 2H), 7.25 (m, 2H), 7.31 (m, 3H),7.61 (d, 1H), 8.22 (s, 1H).

EXAMPLE 41 4108.1002-007 Example 2363-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneusing a procedure analogous to that described in Example 12 Step 2,followed by a procedure analogous to that described in Example 8 Step 2using ammonia. LC-MS Method 2 t_(R)=1.372, min, m/z=448.3; ¹H NMR(CDCl₃) 1.52 (d, 3H), 1.97 (m, 2H), 2.27-2.33 (m, 4H), 2.43 (m, 1H),2.97 (m, 1H), 5.13 (s, 1H), 5.24 (s, 1H), 5.66 (m, 1H), 6.92-7.08 (m,4H), 7.22 (m, 2H), 7.31 (m, 2H), 7.48 (m, 1H), 7.97 (m, 1H), 8.57 (m,1H), 8.74 (m, 1H).

EXAMPLE 42 4108.1002-007 Example 244(R)-6-allyl-3-((S)-1-(4-(2,4-dimethylthiazol-5-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-oneand 2,4-dimethylthiazole-5-boronic acid following a procedure analogousto that described in Example 14. LC-MS Method 1 t_(R)=1.82, min,m/z=451; ¹H NMR (CDCl₃) 7.26 (t, 2H), 7.13 (d, 2H), 7.03 (t, 2H), 6.91(d, 2H), 5.76-5.64 (m, 2H), 5.06 (dd, 2H), 2.98 (m, 1H), 2.74 (s, 3H),2.42 (s, 3H), 1.53 (d, 3H).

EXAMPLE 43 4108.1002-007 Example 258(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one

(R)-6-Allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(20 mg, 0.048 mmol), 3-(trifluoromethyl)-1H-pyrazole (20 mg, 3 equiv.),CuI (1.4 mg, 15% mol), (1R,2R)-(−)-1,2-transcyclohexanediamine (2 mg,30% mol), K₃PO₄ (20 mg, 2 equiv.) were mixed with dry toluene (2 mL) andheated in Microwave Oven for 1 h at 130° C. LC-MS found product peak.The mixture was diluted with EtOAc (8 mL), washed by water (2 mL), brine(3 mL) and dried over Na₂SO₄. After filtration and concentration, theresidue was purified chromatography on a 4-g silica gel cartridge elutedwith a gradient from 5 to 55% EtOAc in gexanes to afford(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one(9.7 mg, 43%) product. LC-MS Method 1 t_(R)=2.05, min, m/z=474; ¹H NMR(CDCl₃) 7.86 (s, 1H), 7.43 (d, 2H), 7.26 (t, 2H), 7.01 (dd, 2H), 6.69(d, 1H), 5.76-5.64 (m, 2H), 5.05 (dd, 2H), 2.95 (m, 1H), 2.65-2.51 (m,2H), 1.54 (d, 3H).

EXAMPLE 44 4108.1002-007 Example 281(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 2-trifluoromethylpyridine-3-boronic acid following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 3t_(R)=1.36 min, m/z=459.3; ¹H NMR (CDCl₃) 1.40 (m, 1H), 1.51 (m, 3H),1.63 (m, 1H), 1.70-1.98 (m, 3H), 2.11-2.33 (m, 3H), 2.95 (m, 1H),3.50-3.63 (m, 2H), 5.66 (m, 1H), 6.97 (m, 4H), 7.20 (m, 2H), 7.29 (m,2H), 7.67 (m, 1H), 7.87-7.90 (m, 1H), 8.78 (m, 1H).

EXAMPLE 45 4108.1002-007 Example 291(R)-3-((S)-1-(4-(1H-pyrazol-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand pyrazole-3-boronic acid using a procedure analogous to thatdescribed in Example 1 Step 2 followed by a procedure analogous to thatdescribed in Example 12 Step 1. LC-MS Method 2 t_(R)=1.808 min,m/z=362.2; ¹H NMR (CDCl₃) 1.48 (d, 3H), 1.60-1.72 (m, 2H), 1.90 (m, 2H),2.22 (m, 3H), 2.84 (m, 1H), 3.46-3.54 (m, 2H), 5.61 (q, 1H), 6.48 (s,1H), 6.89 (d, 2H), 7.19-7.30 (m, 6H), 7.43 (d, 2H), 7.52 (s, 1H).

EXAMPLE 46 4108.1002-007 Example 292(R)-6-allyl-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand 5-fluoropyridine-3-boronic acid using a procedure analogous to thatdescribed in Example 14. LC-MS Method 1 t_(R)=1.84 min, m/z=417 (M+1);¹H NMR (CDCl₃) 8.58 (s, 1H), 8.45 (d, 1H, J=3 Hz), 7.57-7.54 (m, 1H),7.39-7.30 (m, 5H), 7.27-7.25 (m, 2H), 6.93 (d, 2H, J=8 Hz), 5.80-5.68(m, 2H), 5.11-5.03 (m, 2H), 2.97-2.91 (m, 1H), 2.69-2.55 (m, 2H),2.41-2.21 (m, 3H), 1.55 (d, 3H, J=7 Hz).

EXAMPLE 47 4108.1002-007 Example 2953-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneusing a procedure analogous to that described in Example 12 Step 2,followed by a procedure analogous to that described in Example 8 Step 2using ammonia. LC-MS Method 2 t_(R)=1.381 min, m/z=430.2; ¹H NMR (CDCl₃)1.56 (m, 3H), 1.92-2.03 (m, 3H), 2.18-2.37 (m, 5H), 2.51 (m, 1H), 2.94(m, 1H), 5.29-5.61 (m, 2H), 5.71 (m, 1H), 7.03 (m, 2H), 7.21-7.38 (m,8H), 7.77 (m, 1H), 8.53 (m, 1H), 8.72 (s, 1H).

EXAMPLE 48 4108.1002-007 Example 2963-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-oneemploying a procedure analogous to that described in Example 12 Step 2,followed by a procedure analogous to that described in Example 8 Step 2using ammonia. LC-MS Method 2 t_(R)=1.327 min, m/z=430.2; ¹H NMR (CDCl₃)1.49 (m, 3H), 1.93 (m, 1H), 2.12-2.34 (m, 5H), 2.44 (m, 1H), 2.94 (m,1H), 5.46 (m, 2H), 5.67 (m, 1H), 7.08 (m, 2H), 7.19-7.42 (m, 5H), 7.45(m, 2H), 7.80 (m, 2H), 8.76 (m, 2H).

EXAMPLE 49 4108.1002-007 Example 298(R)-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-onefollowing a procedure analogous to that described in Example 12 Step 1.LC-MS Method 1 t_(R)=1.5 min, m/z=457 (M+Na); ¹H NMR (CDCl₃) 8.64 (s,1H), 8.50 (s, 1H), 7.74-7.71 (dd, 1H, J=2, 9 Hz), 7.41-7.27 (m, 7H),7.05 (dd, 2H, J=3, 8 Hz), 5.74-5.68 (m, 1H), 4.27-4.24 (t, 1H, J=6, 6Hz), 3.60-3.57 (t, 1H, J=6, 6 Hz), 2.98-2.93 (m, 1H), 2.38-2.20 (m, 3H),2.10-1.93 (m, 3H), 1.73-1.70 (1H, m), 1.57 (d, 3H, J=7 Hz), 1.41-1.37(m, 1H).

EXAMPLE 50 4108.1002-007 Example 3003-(4-((S)-1-((R)-6-(3-amino-3-oxopropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine1-oxide

The title compound was prepared from3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamidefollowing a procedure analogous to that described 38. LC-MS Method 2t_(R)=1.476 min, m/z=445.2; ¹H NMR (CDCl₃) 1.56 (d, 3H), 1.98-2.15 (m,1H), 2.18-2.37 (m, 5H), 2.47-2.58 (m, 1H), 2.96 (m, 1H), 5.51 (s, 1H),5.57 (s, 1H), 5.70 (q, 1H), 7.03 (q, 2H), 7.26-7.38 (m, 9H), 8.20 (d,1H), 8.49 (s, 1H).

EXAMPLE 51 4108.1002-007 Example 302(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-oneand 5-fluoropyridine-3-boronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.84 min, m/z=435(M+1); ¹H NMR (CDCl₃) 8.58 (t, 1H, J=1.5, 1.5 Hz), 8.44 (d, 1H, J=3 Hz),7.51-7.48 (ddd, 1H, J=9, 4, 2 Hz), 7.33-7.262 (m, 4H), 7.04 (at, J=9, 9Hz), 6.98 (d, 2H, 8 Hz), 5.76-5.66 (m, 2H), 5.11-5.00 (m, 2H), 3.00-2.95(m, 1H), 2.65-2.5 (m, 2H), 2.41-2.33 (m, 1H) 2.31-2.18 (m, 2H), 1.55 (d,3H, J=7 Hz).

EXAMPLE 52 4108.1002-007 Example 3043-((R)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamideand 6-methoxypyridine-3-boronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 3 t_(R)=1.106 min, m/z=460.2;¹H NMR (CD₃OD) 1.54 (m, 3H), 1.95 (m, 1H), 2.16-2.29 (m, 4H), 2.40 (m,2H), 2.44 (m, 1H), 3.10 (m, 1H), 3.99 (s, 3H), 5.56 (m, 1H), 6.94 (m,1H), 7.03 (m, 2H), 7.28-7.39 (m, 8H), 7.93 (m, 1H), 8.28 (m, 1H).

EXAMPLE 53 4108.1002-007 Example 305(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(5-methoxypyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 5-methoxypyridine-3-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.694 min,m/z=465.2; ¹H NMR (CDCl₃) 1.34 (m, 1H), 1.53 (m, 3H), 1.68 (m, 1H), 1.94(m, 3H), 2.18-2.32 (m, 3H), 2.95 (m, 1H), 3.56 (m, 2H), 3.88 (s, 3H),5.69 (m, 1H), 7.01 (m, 4H), 7.24 (m, 3H), 7.31 (m, 2H), 8.25 (m, 1H),8.34 (m, 1H).

EXAMPLE 54 4108.1002-007 Example 306(R)-6-allyl-3-((S)-1-(4-(5-chloropyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 5-chloropyridine-3-boronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.97 min, m/z=451(M+1); ¹H NMR (CDCl₃) 8.68 (d, 1H, J=2 Hz), 8.59 (d, 1H, J=2 Hz), 7.94(t, 1H, J=2.2 Hz), 7.33-7.27 (m, 4H), 7.04 (ap q, 2H, J=9, 17 Hz),5.75-5.65 (m, 2H), 5.12-5.02 (m, 2H), 3.03-2.98 (m, 1H), 2.66-2.54 (m,2H), 2.41-2.17 (m, 3H), 1.56 (d, 3H, J=7 Hz).

EXAMPLE 55 4108.1002-007 Example 307N-(2-((S)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)ethyl)methanesulfonamide

The title compound was prepared from(R)-6-(2-aminoethyl)-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneby treatment with MeSO₂Cl. LC-MS Method 2 t_(R)=1.525 min, m/z=480.2; ¹HNMR (CDCl₃) 1.52 (d, 3H), 2.05-2.32 (m, 6H), 2.81 (s, 3H), 2.86 (m, 1H),2.93-3.04 (m, 1H), 3.06-3.20 (m, 1H), 4.73 (s, 1H), 5.63 (q, 1H), 6.95(d, 2H), 7.05-7.22 (m, 2H), 7.23-7.40 (m, 6H), 7.71 (d, 1H), 8.50 (d,1H), 8.66 (s, 1H).

EXAMPLE 56 4108.1002-007 Example 311(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.29 min, m/z=431(M+1); ¹H NMR (CDCl₃) 8.71 (d, 1H, J=6 Hz), 7.78 (d, 1H, J=6 Hz), 7.7(s, 1H), 7.49 (t, 2H, J=7, 7 Hz), 7.27-7.24 (m, 2H), 7.17 (m, 2H),7.09-7.02 (aq, 2H, J=9, 17 Hz), 5.73 (q, 1H, J=7, 14 Hz), 4.27 (t, 1H,J=6, 6 Hz), 3.60 (t, 1H, J=6, 6 Hz), 3.09-3.03 (m, 1H), 2.95 (s, 3H),2.41-2.25 (m, 3H), 2.06-1.90 (m, 2H) 1.73-1.64 (m, 1H), 1.58 (d, 3H, J=7Hz), 1.40-1.33 (m, 1H).

EXAMPLE 57 4108.1002-007 Example 430(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-oneand pyridine-2-boronic acid following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.462 min,m/z=420.18; ¹H NMR (CDCl₃) 1.48 (d, 3H), 2.03-2.30 (m, 5H), 2.85 (m,1H), 3.50 (m, 1H), 3.72 (m, 1H), 5.65 (m, 1H), 6.98 (m, 4H), 7.24 (m,2H), 7.60 (m, 1H), 7.74 (m, 3H), 8.62 (m, 1H).

EXAMPLE 58 4108.1002-007 Example 431(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-oneand pyridine-2-boronic acid following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.049 min, m/z=391;¹H NMR (CDCl₃) 1.06-1.19 (d, 6H), 1.50 (s, 3H), 2.11-2.38 (m, 6H), 2.80(m, 1H), 5.66 (m, 1H), 6.97 (m, 2H), 7.04 (d, 2H), 7.18 (m, 1H), 7.23(m, 2H), 7.58 (m, 1H), 7.73 (m, 3H), 8.60 (d, 1H).

EXAMPLE 59 4108.1002-007 Example 432(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand pyridine-2-boronic acid following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=0.905 min,m/z=435.2; ¹H NMR (CDCl₃) 1.22-1.37 (m, 1H), 1.49 (d, 3H), 1.60-1.70 (m,2H), 1.80-1.97 (m, 2H), 2.07-2.31 (m, 3H), 2.85 (m, 1H), 3.50 (m, 2H),5.65 (m, 1H), 6.97 (m, 4H), 7.20 (m, 3H), 7.57-7.70 (m, 4H), 8.60 (m,1H).

EXAMPLE 60 4108.1002-007 Example 4333-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamideand pyridine-2-boronic acid following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=0.976 min, m/z=448;¹H NMR (CDCl₃) 1.50 (d, 3H), 1.91 (m, 1H), 2.17-2.23 (m, 5H), 2.41 (m,1H), 2.86 (m, 1H), 5.18 (m, 1H), 5.32 (m, 1H), 5.66 (m, 1H), 7.00 (m,4H), 7.18 (m, 3H), 7.57 (d, 1H), 7.69 (m, 3H), 8.58 (d, 1H).

EXAMPLE 61 4108.1002-007 Example 434N-(3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamideand pyridine-2-boronic acid following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.036 min,m/z=512.1; ¹H NMR (CDCl₃) 1.49 (d, 3H), 1.60-1.70 (m, 1H), 1.84 (m, 1H),1.89-1.99 (m, 2H), 2.10-2.20 (m, 2H), 2.25 (m, 1H), 2.74 (s, 3H), 3.01(m, 2H), 4.22 (m, 1H), 5.64 (m, 1H), 6.97 (m, 4H), 7.16 (m, 3H), 7.58(d, 1H), 7.70 (m, 3H), 8.60 (m, 1H).

EXAMPLE 62 4108.1002-007 Example 435(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-methylpyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 6-methylpyridine-2-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.868 min,m/z=449.2; ¹H NMR (CD₃OD) 1.28 (m, 1H), 1.56 (d, 3H), 1.61 (m, 1H), 1.95(m, 2H), 2.23 (m, 1H), 2.34 (m, 1H), 2.46 (m, 1H), 2.55 (s, 3H), 3.11(m, 1H), 3.46 (m, 2H), 5.50 (m, 1H), 7.06 (m, 4H), 7.19 (d, 1H), 7.31(m, 2H), 7.51 (d, 1H), 7.73 (m, 3H).

EXAMPLE 63 4108.1002-007 Example 436(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-oneand 6-methoxypyridine-3-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.887 min,m/z=450.2; ¹H NMR (CDCl₃) 1.54 (d, 3H), 2.07-2.29 (m, 2H), 2.34 (m, 3H),2.97 (m, 1H), 3.55 (m, 1H), 3.74 (m, 1H), 4.06 (d, 3H), 5.64 (m, 1H),6.93 (m, 1H), 6.95-7.11 (m, 2H), 7.26-7.37 (m, 2H), 7.90 (m, 1H), 8.38(m, 1H).

EXAMPLE 64 4108.1002-007 Example 437(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-oneand 6-methoxypyridine-3-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 3 t_(R)=1.111 min,m/z=478.23; ¹H NMR (CDCl₃) 1.15 (d, 6H), 1.55 (d, 3H), 2.17-2.29 (m,4H), 2.42 (m, 1H), 2.91 (m, 1H), 3.95 (s, 3H), 5.70 (m, 1H) 6.80 (d,1H), 7.03 (m, 4H), 7.30 (m, 4H), 7.71 (m, 1H), 8.30 (s, 1H).

EXAMPLE 65 4108.1002-007 Example 438(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 6-methoxypyridine-3-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.3 min,m/z=487.1; ¹H NMR (CD₃OD) 1.25-1.37 (m, 1H), 1.55 (d, 3H), 1.61 (m, 1H),1.95 (m, 2H), 2.17-2.28 (m, 1H), 2.36 (m, 1H), 2.48 (m, 1H), 3.12 (m,1H), 3.48 (m, 2H), 3.94 (s, 3H), 5.58 (m, 1H), 6.86 (d, 1H), 7.07 (m,4H), 7.35 (m, 4H), 7.86 (dd, 1H), 8.28 (s, 1H).

EXAMPLE 66 4108.1002-007 Example 4393-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamideand 6-methoxypyridine-3-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.254 min,m/z=477.21; ¹H NMR (CDCl₃) 1.55 (d, 3H), 2.01 (m, 1H), 2.15-2.34 (m,5H), 2.46 (m, 1H), 2.96 (m, 1H), 4.00 (s, 3H), 5.66 (m, 1H), 5.80 (s,1H), 6.19 (s, 1H), 6.86 (d, 1H), 7.03 (m, 4H), 7.23 (m, 2H), 7.79 (dd,1H), 8.36 (s, 1H).

EXAMPLE 67 4108.1002-007 Example 440N-(3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamideand 6-methoxypyridine-3-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.327 min,m/z=542.1; ¹H NMR (CD₃OD) 1.33 (m, 1H), 1.58 (d, 3H), 1.66 (m, 1H), 1.98(m, 2H), 2.20-2.39 (m, 2H), 2.47 (m, 1H), 2.87 (s, 3H), 2.99 (m, 2H),3.15 (m, 1H), 3.96 (s, 3H), 5.60 (m, 1H), 6.87 (d, 1H), 7.12 (m, 4H),7.36 (m, 4H), 7.87 (d, 1H), 8.29 (s, 1H).

EXAMPLE 68 4108.1002-007 Example 4413-(4-((S)-1-((R)-6-(3-amino-3-oxopropyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine1-oxide

To a solution of3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide (70 mg, 0.16 mmol) in CH₂Cl₂ (10 mL), was added m-CPBA (135mg, 0.79 mmol), and the reaction mixture was stirred at rt for 3 h.After the solvent was removed under reduced pressure, the residue waspurified by preparative TLC to afford3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoicacid (10 mg, 15%). LC-MS Method 2 t_(R)=0.987 min, m/z=464.17; ¹H NMR(CDCl₃): 1.51 (m, 3H), 1.92 (m, 1H), 2.12-2.28 (m, 5H), 2.43 (m, 1H),2.95 (m, 1H), 5.56 (m, 1H), 5.65 (m, 1H), 5.31 (m, 1H), 6.95 (m, 2H),7.08 (m, 2H), 7.15 (m, 1H), 7.20 (m, 1H), 7.25 (m, 2H), 7.56 (m, 1H),7.24 (m, 1H), 8.35 (m, 1H), 8.65 (m, 1H).

EXAMPLE 69 4108.1002-007 Example 442(R)-3-((S)-1-(4-(5-chloropyridin-3-yl)phenyl)ethyl)-6-(4-fluoroPhenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 5-chloropyridine-3-boronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.64 min, m/z=469.

EXAMPLE 70 4108.1002-007 Example 4433-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propanoicacid

The title compound was prepared from(R)-6-(4-fluorophenyl)-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-onefollowing a procedure analogous to that described in Example 14. LC-MSMethod 1 t_(R)=1.52 min, m/z=467.

EXAMPLE 71 4108.1002-007 Example 4445-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide

Step 1

To a solution of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(1 g, 2.4 mmol) in dry THF (15 mL) was added dropwise BH₃.THF (5 mL, 1M) at 0° C. After stirring for 2 h at rt, the reaction mixture wascooled to 0° C. and water (1 mL), aqueous NaOH (0.5 mL, 3 M) and H₂O₂(0.5 mL, 30%) were successively added. The mixture was stirred for 2-3 hat rt and diluted with water (8 mL). The pH was adjusted to 6-7 with 0.5N HCl. The layers were separated, and the aqueous phase was extractedwith EtOAc (3×10 mL). The combined organic layers were washed with asatd aq NaHCO₃ (20 mL) and brine (20 mL), dried over Na₂SO₄, andconcentrated in vacuo to give the crude product, which was purified bypreparative TLC to afford(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one(400 mg, 38%).

Step 2

A mixture of(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one(250 mg, 0.6 mmol), 5-(methoxycarbonyl)pyridin-3-ylboronic acid (163 mg,0.9 mmol), PdCl₂(PPh₃)₂ (50 mg, 20%) and aqueous Cs₂CO₃ solution (2 M, 2mL) in 1,4-dioxane (6 mL) was heated to reflux at 100° C. overnightunder N₂. The mixture was filtered, and the filtrate was extracted withEtOAc for 3 times. The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated to the crude product, which waspurified by preparative HPLC to give methyl5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate(220 mg, crude).

Step 3

Methyl5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate(30 mg, 0.1 mmol) was dissolved in anhydrous NH₃ in EtOH (5 mL). Thenthe mixture was stirred at rt overnight. The solvent was removed invacuo to give the crude product, which was purified by preparative HPLCto provide5-(4-((S)-1-((R)-6-(4-luorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide(10 mg, 34%). LC-MS Method 2 t_(R)=1.022 min, m/z=478; ¹H NMR (CD₃OD):1.31 (m, 1H), 1.56 (m, 3H), 1.59 (m, 1H), 1.91 (m, 2H), 2.17-2.28 (m,1H), 2.33 (m, 1H), 2.44 (m, 1H), 3.14 (m, 1H), 3.44 (m, 2H), 5.60 (m,1H), 7.04-7.17 (m, 4H), 7.29 (m, 2H), 7.49 (m, 2H), 8.41 (m, 1H), 8.86(m, 1H), 8.97 (m, 1H).

EXAMPLE 72 4108.1002-007 Example 4455-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)-N,N-dimethylnicotinamide

The title compound was prepared methyl5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinatefollowing a procedure analogous to that described in Example 71 Step 3using dimethylamine in place of ammonia. LC-MS Method 2 t_(R)=1.086 min,m/z=506.3; ¹H NMR (CDCl₃) 0.87 (m, 1H), 1.21-1.37 (m, 4H), 1.64 (m, 1H),1.98 (m, 2H), 2.22 (m, 1H), 2.35 (m, 1H), 2.54 (m, 1H), 2.65 (m, 1H),3.05 (m, 3H), 3.15 (m, 4H), 3.45 (m, 2H), 5.63 (m, 1H), 7.03-7.18 (m,4H), 7.34 (m, 2H), 7.49 (m, 2H), 8.06 (m, 1H), 8.58 (m, 1H), 8.81 (m,1H).

EXAMPLE 73 Example 4108.1002-007 Example 4465-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)-N-methylnicotinamide

The title compound was prepared methyl5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinatefollowing a procedure analogous to that described in Example 71 Step 3using methylamine in place of ammonia. LC-MS Method 2 t_(R)=1.055 min,m/z=491.12; ¹H NMR (CD₃OD) 1.18 (m, 1H), 1.48 (d, 3H), 1.51 (m, 1H),1.85 (m, 2H), 2.13 (m, 1H), 2.25 (m, 1H), 2.48 (m, 1H), 2.88 (s, 3H),3.09 (m, 1H), 3.38 (m, 2H), 5.51 (m, 1H), 6.98-7.07 (m, 4H), 7.22 (m,2H), 7.42 (m, 2H), 8.28 (m, 1H), 8.75 (s, 1H), 8.82 (s, 1H).

EXAMPLE 74 4108.1002-007 Example 4473-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamideand pyridine-4-boronic acid following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=0.906 min,m/z=448.1; ¹H NMR (CDCl₃) 1.59 (d, 3H), 2.15 (m, 1H), 2.24-2.32 (m, 4H),2.45 (m, 1H), 3.07 (m, 2H), 5.66 (m, 1H), 5.71 (m, 1H), 5.84 (m, 1H),7.03 (m, 2H), 7.05 (m, 2H), 7.22 (m, 1H), 7.25 (m, 1H), 7.50 (d, 2H),7.93 (d, 2H), 8.84 (d, 2H).

EXAMPLE 75 4108.1002-007 Example 448(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.945 min,m/z=435.5; ¹H NMR (CD₃OD) 1.56 (d, 3H), 1.92 (m, 1H), 2.01 (m, 1H), 2.17(m, 2H), 2.36 (m, 2H), 2.48 (m, 1H), 2.56 (m, 3H), 3.12 (m, 1H), 3.62(m, 1H), 5.62 (m, 1H), 7.05 (m, 4H), 7.30 (m, 2H), 7.44 (m, 1H), 7.54(m, 3H), 8.39 (s, 2H).

EXAMPLE 76 4108.1002-007 Example 449(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.976 min,m/z=463.8; ¹H NMR (CDCl₃) 1.09 (d, 6H), 1.49 (d, 3H), 2.16 (m, 4H), 2.35(m, 1H), 2.56 (d, 3H), 2.85 (m, 1H), 5.65 (m, 1H), 6.94-7.05 (m, 4H),7.17-7.26 (m, 4H), 7.34 (d, 2H), 8.47 (d, 1H).

EXAMPLE 77 4108.1002-007 Example 4503-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propanoicacid

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-onefollowing procedures analogous to those described in Example 12 Step 2.LC-MS Method 1 t_(R)=1.05 min, m/z=463.

EXAMPLE 78 4108.1002-007 Example 4513-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propanoicacid following procedures analogous to those described in Example 1 Step2. LC-MS Method 2 t_(R)=0.793 min, m/z=462.2; ¹H NMR (CDCl₃) 1.51 (d,3H), 2.12-2.38 (m, 6H), 2.43 (m, 1H), 2.61 (s, 3H), 2.89 (m, 1H),5.10-5.34 (d, 2H), 5.66 (m, 1H), 6.99 (m, 4H), 7.17-7.27 (m, 4H), 7.36(d, 2H), 8.46 (d, 1H).

EXAMPLE 79 4108.1002-007 Example 452(R)-6-(4-fluorophenyl)-6-(3-hydroxy-3-methylbutyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-oneby treatment with (i) Jones reagent, (ii) MeOH, SOCl₂ and (iii) MeMgBr.LC-MS Method 2 t_(R)=0.992 min, m/z=477.5; ¹H NMR (CDCl₃) 1.08 (d, 6H),1.15 (m, 1H), 1.52 (d, 3H), 1.59 (m, 1H), 1.84-2.01 (m, 2H), 2.15-2.34(m, 3H), 2.83 (s, 3H), 2.98 (m, 1H), 5.67 (m, 1H), 6.96 (t, 2H), 7.09(d, 2H), 7.20 (m, 2H), 7.41 (d, 2H), 7.65 (d, 2H), 8.75 (s, 1H).

EXAMPLE 80 4108.1002-007 Example 453N-(3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamideand 2-methylpyridine-4-boronic acid Example 1 Step 2. LC-MS Method 2t_(R)=0.964 min, m/z=525.21; ¹H NMR (CDCl₃) 1.31-1.43 (m, 1H), 1.50 (d,3H), 1.62 (m, 2H), 1.07-2.09 (m, 2H), 2.13-2.47 (m, 3H), 2.83 (d, 6H),3.01 (m, 3H), 4.35 (s, 1H), 5.66 (m, 1H) 7.07 (m, 2H), 7.14 (m, 2H),7.29 (m, 5H), 7.44 (m, 2H), 7.65 (m, 1H), 7.73 (d, 1H), 8.78 (d, 1H).

EXAMPLE 81 4108.1002-007 Example 454(R)-3-((S)-1-(4-(2,6-dimethylpyridin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyridine-N-oxide using a procedure analogous tothat described in Example 14, followed by treatment with disiamylborane. LC-MS Method 1 t_(R)=1.1 min, m/z=463 (M+1); ¹H NMR (CDCl₃) 7.50(s, 2H), 7.45 (d, 1H), 7.25 (m, 3H), 7.17-6.99 (m, 4H), 5.73 (q, 1H),4.28 (t, 1H), 3.04 (m, 1H), 2.82 (s, 6H), 2.31 (m, 3H), 1.91 (m, 3H),1.58 (d, 3H).

EXAMPLE 82 4108.1002-007 Example 455(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(thiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

A mixture of(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one(0.4910 g, 1.17 mmol, 1.0 equiv), bis(pinacolato)diboron (0.3925 g, 1.55mmol, 1.3 equiv), KOAc (0.3696 g, 3.76 mmol, 3.2 equiv), andPdCl₂(dppf).CH₂Cl₂ (0.0316 g, 0.0386 mmol, 0.033 equiv) in DMSO (6 mL)was heated at 90° C. under N₂ for 20 h. After cooling, the reactionmixture was partitioned between EtOAc and water. The organic phase waswashed with brine, and dried over Na₂SO₄. After the solvents wereevaporated, the residue was purified by chromatography on silica geleluted with hexanes/ethyl acetate to give 0.4776 g (87%) of(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneas a white solid.

Step 2

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(20 mg, 0.043 mmol), 2-bromothiazole (14 mg, 2 equiv), 2M aq Na₂SO₄solution (0.5 mL) and Pd(PPh₃)₂Cl₂ were mixed with THF (0.6 mL) andheated in a microwave oven for 2 h at 140° C. LC-MS found reactioncompleted. The mixture was diluted with EtOAc (8 mL), washed with water(2 mL), 1% aq HCl (2 mL) and brine (1.5 mL). After concentration, theresidue was purified by preparative HPLC to afford(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(thiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(6.0 mg, 33%). LC-MS (3 min) t_(R)=1.86 min, m/z=423 (M+1).

Step 3

(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(thiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(6.0 mg, 0.014 mmol) was dissolved in dry THF (2 mL) and cooled to 0° C.BH₃-THF (1.0M, 100 μL, excess) was added slowly. After 10 min, themixture was warmed to it and stirred for 3 h. LC-MS found reactioncompleted. The mixture was quenched with water (1 mL). NaBO₃ (ca 4 mg)was added. The mixture was stirred 40 min, filtered, concentrated andpurified by preparative HPLC to afford(R)-3-((S)-1-(4-(2,6-dimethylpyridin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one(3.4 mg, 54%), LC-MS (3 min) t_(R)=1.86 min, m/z=423 (M+1). LC-MS Method1 t_(R)=1.86 min, m/z=423 (M+1); ¹H NMR (CDCl₃) 7.71 (m, 2H), 7.40-7.22(m, 4H), 7.16-7.03 (m, 3H), 6.96 (m, 1H), 5.66 (m, 1H), 2.96 (m, 1H),1.54 (d, 3H).

EXAMPLE 83 4108.1002-007 Example 456(R)-3-((S)-1-(4-(2,4-dimethylthiazol-5-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-oneand 2,4-dimethylthiazole-5-boronic acid using a procedure analogous tothat described in Example 14, followed by a procedure analogous to thatdescribed in Example 12. LC-MS Method 1 t_(R)=1.49 min, m/z=469; ¹H NMR(CDCl₃) 7.28 (m, 2H), 7.15 (d, 2H), 7.03 (q, 4H), 5.68 (q, 1H), 3.59 (t,1H), 3.02 (m, 1H), 2.91 (s, 3H), 2.48 (s, 3H), 1.55 (d, 3H).

EXAMPLE 84 4108.1002-007 Example 4573-((R)-3-((S)-1-(4-(2,4-dimethylthiazol-5-yl)phenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from(R)-3-((S)-1-(4-(2,4-dimethylthiazol-5-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneemploying a procedure analogous to that described in Example 12 Step 2,followed by a procedure analogous to that described in Example 8 Step 2using ammonia. LC-MS Method 1 t_(R)=1.38 min, m/z=482 (M+1); ¹H NMR(CDCl₃) 7.32 (m, 5H), 7.18 (d, 2H), 7.04 (m, 4H), 5.69 (q, 1H), 2.84 (s,3H), 2.45 (s, 3H), 2.02 (m, 1H), 1.55 (d, 3H).

EXAMPLE 85 4108.1002-007 Example 468(S)-6-(2-hydroxyethyl)-6-phenyl-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-oneand pyridine-2-boronic acid following procedures analogous to thosedescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=0.976 min,m/z=805.3; ¹H NMR (CDCl₃) 1.50 (d, 2H), 2.06-2.19 (m, 2H), 2.26 (m, 3H),2.83 (m, 1H), 3.53 (m, 1H), 3.71 (m, 1H), 5.64 (m, 1H), 6.94 (d, 2H),7.14 (m, 1H), 7.24 (m, 3H), 7.28 (m, 2H), 7.56 (d, 2H), 7.67 (m, 3H),8.59 (d, 1H).

EXAMPLE 86 4108.1002-007 Example 469(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-oneand pyridine-2-boronic acid following procedures analogous to thosedescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.542 min,m/z=430.23; ¹H NMR (CDCl₃) 1.02-1.15 (d, 6H), 1.50 (d, 3H), 2.09-2.21(m, 6H), 2.32 (m, 1H), 2.78 (m, 1H), 5.65 (m, 1H), 6.98 (d, 2H),7.15-7.30 (m, 6H), 7.55 (m, 1H), 7.70 (d, 1H), 8.60 (d, 1H).

EXAMPLE 87 4108.1002-007 Example 470(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-oneand pyridine-2-boronic acid following procedures analogous to thosedescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.01 min,m/z=416.21; ¹H NMR (CD₃OD) 1.30 (m, 1H), 1.55 (d, 3H), 1.62 (m, 1H),1.94 (m, 2H), 2.20 (m, 1H), 2.32 (m, 1H), 2.48 (m, 1H), 3.09 (m, 1H),3.44 (m, 2H), 5.57 (m, 1H), 7.03 (d, 2H), 7.29-7.40 (m, 6H), 7.67 (d,2H), 7.73 (d, 1H), 7.84 (t, 1H), 8.55 (d, 1H).

EXAMPLE 88 4108.1002-007 Example 4713-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamideand pyridine-2-boronic acid following procedures analogous to thosedescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=0.932 min,m/z=430.1; ¹H NMR (CDCl₃) 1.52 (d, 3H), 1.90 (m, 1H), 2.13 (m, 1H), 2.21(m, 4H), 2.45 (m, 1H), 2.82 (m, 1H), 5.15 (s, 1H), 5.35 (s, 1H), 5.65(m, 1H), 6.98 (d, 2H), 7.13-7.32 (m, 6H), 7.56 (m, 1H), 7.65 (m, 3H),8.57 (d, 1H).

EXAMPLE 89 4108.1002-007 Example 472N-(3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamideand pyridine-2-boronic acid following procedures analogous to thosedescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.017 min,m/z=494.1; ¹H NMR (CDCl₃) 1.37-1.48 (m, 1H), 1.49 (d, 3H), 1.67 (m, 1H),1.82-1.99 (m, 2H), 2.05-2.18 (m, 1H), 2.12-2.23 (m, 2H), 2.82 (m, 4H),3.00 (m, 2H), 4.25 (m, 1H), 5.65 (m, 1H), 6.96 (d, 2H), 7.14-7.29 (m,6H), 7.55 (d, 1H), 7.65 (m, 3H), 8.58 (d, 1H).

EXAMPLE 90 4108.1002-007 Example 473(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-methylpyridin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-oneand 6-methylpyridine-2-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.986 min,m/z=431.1; ¹H NMR (CDCl₃) 1.33 (m, 2H), 1.52 (d, 3H), 1.69 (m, 1H), 1.97(m, 2H), 2.12-2.30 (m, 3H), 2.56 (s, 3H), 2.85 (m, 1H), 3.52 (t, 2H),5.67 (m, 1H), 6.95 (d, 2H), 7.03 (d, 1H), 7.22-7.37 (m, 6H), 7.55 (t,1H), 7.64 (d, 2H).

EXAMPLE 91 4108.1002-007 Example 474N-(3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamideand pyridine-3-boronic acid following procedures analogous to thosedescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.466 min,m/z=497.3; ¹H NMR (CDCl₃) 1.33 (m, 1H), 1.53 (d, 3H), 1.63 (m, 1H),1.84-2.03 (m, 2H), 2.18 (m, 1H), 2.30 (m, 2H), 2.84 (s, 3H), 2.93 (m,1H), 3.02 (t, 2H), 4.30 (s, 1H), 5.64 (m, 1H), 7.02 (d, 2H), 7.22 (m,2H), 7.31 (m, 5H), 7.77 (m, 1H), 7.80 (d, 1H), 8.71 (d, 1H), 8.93 (s,1H).

EXAMPLE 92 4108.1002-007 Example 475(S)-6-(2-hydroxyethyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-oneand 6-methoxypyridine-3-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.269 min,m/z=432.2; ¹H NMR (CDCl₃) 1.50 (d, 3H), 2.05-2.35 (m, 5H), 2.90 (m, 1H),3.51 (m, 1H), 3.70 (m, 1H), 3.97 (s, 3H), 5.63 (m, 1H), 6.85 (d, 1H),6.92 (m, 2H), 7.17-7.35 (m, 6H), 7.81 (d, 1H), 8.32 (s, 1H).

EXAMPLE 93 4108.1002-007 Example 476(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-oneand 6-methoxypyridine-3-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.989 min,m/z=403.1; ¹H NMR (CDCl₃) 1.10 (s, 3H), 1.17 (s, 3H), 1.52 (d, 3H),2.13-2.28 (m, 6H), 2.47 (m, 1H), 2.87 (m, 1H), 3.95 (s, 3H), 5.70 (m,1H), 6.79 (d, 1H), 7.02 (d, 2H), 7.21-7.38 (m, 6H), 7.58 (d, 1H), 8.27(d, 1H).

EXAMPLE 94 Example 4108.1002-007 Example 477N-(3-((R)-3-((S)-1-(4-(6-methoxypyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamideand 6-methoxypyridine-3-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.316 min,m/z=524.1; ¹H NMR (CDCl₃) 1.28-1.38 (m, 1H), 1.48 (d, 3H), 1.67 (m, 1H),1.81-1.98 (m, 2H), 2.13 (m, 1H), 2.24 (m, 2H), 2.83 (m, 4H), 3.01 (m,2H), 3.91 (s, 3H), 4.15 (m, 1H), 5.62 (m, 1H), 6.73 (d, 1H), 6.91 (d,2H), 7.18-7.32 (m, 7H), 7.62 (dd, 1H), 8.21 (s, 1H).

EXAMPLE 95 4108.1002-007 Example 478(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-oneand 6-aminopyridine-3-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.963 min,m/z=431.8; ¹H NMR (CDCl₃) 1.36 (d, 3H), 1.75 (m, 1H), 1.98 (m, 3H), 2.21(m, 1H), 2.38 (m, 2H), 2.89 (m, 1H), 3.56 (m, 2H), 5.05 (s, 1H), 5.65(m, 1H), 6.62 (d, 1H), 6.97 (d, 2H), 7.17 (d, 2H), 7.20-7.39 (m, 5H),7.63 (d, 1H), 8.12 (s, 1H).

EXAMPLE 96 4108.1002-007 Example 479(S)-6-(2-hydroxyethyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.928 min,m/z=444.4; ¹H NMR (CDCl₃) 1.50 (d, 3H), 2.05-2.18 (m, 2H), 2.26-2.39 (m,6H), 2.82 (s, 3H), 2.94 (m, 1H), 3.51 (m, 1H), 3.72 (m, 1H), 5.54 (m,1H), 7.00 (d, 2H), 7.24-7.38 (m, 7H), 7.57 (s, 1H), 7.64 (d, 1H), 8.75(d, 1H).

EXAMPLE 97 4108.1002-007 Example 480(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.866 min,m/z=444.2; ¹H NMR (CDCl₃) 1.04-1.16 (d, 6H), 1.50 (d, 3H), 2.14-2.25 (m,4H), 2.45 (m, 1H), 2.57 (s, 3H), 2.83 (m, 1H), 5.65 (m, 1H), 7.04 (d,2H), 7.20-7.33 (m, 9H), 8.45 (d, 1H).

EXAMPLE 98 4108.1002-007 Example 4813-((R)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamideand 2-methylpyridine-4-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.917 min,m/z=444.4; ¹H NMR (CDCl₃) 1.51 (d, 3H), 1.92 (m, 1H), 2.13-2.32 (m, 5H),2.44 (m, 1H), 2.82 (s, 3H), 2.93 (m, 1H), 5.50-5.68 (m, 3H), 7.06 (d,2H), 7.19-7.35 (m, 5H), 7.39 (d, 2H), 7.58 (s, 1H), 7.65 (d, 1H), 8.74(d, 1H).

EXAMPLE 99 4108.1002-007 Example 482N-(3-((R)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamideand 2-methylpyridine-4-boronic acid following procedures analogous tothose described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.988 min,m/z=508.2; ¹H NMR (CDCl₃) 1.36 (m, 1H), 1.51 (d, 3H), 1.70 (m, 1H), 1.96(m, 2H), 2.17 (m, 1H), 2.26 (m, 2H), 2.59 (s, 3H), 2.86 (m, 4H), 3.02(m, 2H), 4.19 (m, 1H), 5.62 (m, 1H), 6.96 (d, 2H), 7.19 (m, 3H), 7.26(d, 2H), 7.29 (m, 4H), 8.47 (d, 1H).

EXAMPLE 100 4108.1002-007 Example 483(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-1H-pyrazol-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand pyrazole-3-boronic acid using a procedure analogous to thatdescribed in Example 1 Step 2, followed by treatment with NaH and MeI,and hydroboration using a procedure analogous to that described inExample 12 Step 1. LC-MS Method 3 t_(R)=1.18 min, m/z=442.1; ¹H NMR(CDCl₃) 1.29 (m, 1H), 1.47 (d, 3H), 1.65 (m, 1H), 1.83-2.03 (m, 3H),2.11 (m, 1H), 2.18-2.37 (m, 3H), 2.75-2.96 (m, 1H), 3.52 (m, 2H), 3.78(m, 1H), 3.91 (s, 1H), 5.63 (m, 1H), 6.41 (s, 1H), 6.87 (d, 2H), 6.94(d, 1H), 7.08 (d, 1H), 7.19-7.37 (m, 7H), 7.43 (d, 2H).

EXAMPLE 101 4108.1002-007 Example 5026-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile

The title compound was prepared from(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-5-cyanopyridine following a procedure analogous to thatdescribed in Example 14. LC-MS Method 1 tR=1.58, m/z=482 (M+Na); 1H NMR(CDCl3) 8.93 (d, 1H), 8.01 (dt, 1H), 7.79 (m, 3H), 7.25 (m, 1H), 7.07(m, 5H), 5.74 (q, 1H), 4.28 (t, 1H), 3.59 (t, 1H), 2.98 (m, 1H), 1.58(d, 3H), 1.53 (m, 1H).

EXAMPLE 102 4108.1002-007 Example 510N-methyl-N-(3-((R)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)acetamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamideand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.98,m/z=486.2; ¹H NMR (CDCl₃) 1.21-1.38 (m, 1H), 1.52 (d, 3H), 1.61-1.90 (m,3H), 2.05 (d, 3H), 2.17 (m, 1H), 2.42 (m, 2H), 2.78 (s, 1H), 2.83 (s,3H), 2.85 (s, 2H), 2.92 (m, 1H), 3.11-3.33 (m, 2H), 5.65 (m, 1H), 7.05(d, 2H), 7.21 (m, 2H), 7.30 (m, 3H), 7.38 (d, 2H), 7.60 (s, 1H), 7.71(d, 1H), 8.72 (d, 1H).

EXAMPLE 103 4108.1002-007 Example 511N-(2-((S)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)methanesulfonamide

The title compound was prepared fromN-(2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)methanesulfonamideand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.12, m/z=494;¹H NMR (CDCl₃) 1.48 (d, 3H), 2.10 (m, 2H), 2.20-2.41 (m, 2H), 2.43 (m,1H), 2.71 (s, 3H), 2.73 (s, 3H), 3.11 (m, 2H), 5.52 (m, 1H), 7.13 (d,2H), 7.25 (m, 3H), 7.34 (m, 2H), 7.62 (d, 2H), 7.91 (m, 1H), 8.08 (s,1H), 8.56 (d, 1H).

EXAMPLE 104 Example 4108.1002-007 Example 512(R)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.992,m/z=498.1; ¹H NMR (CDCl₃) 1.21 (m, 3H), 1.48 (d, 3H), 1.61-1.95 (m, 5H),2.12 (m, 1H), 2.26 (m, 4H), 2.52 (s, 3H), 2.83 (m, 1H), 3.11 (m, 3H),3.22 (m, 1H), 5.67 (m, 1H), 6.95 (d, 2H), 7.18 (m, 1H), 7.21 (m, 1H),7.23 (m, 2H), 7.29 (m, 3H), 7.30 (m, 2H), 8.41 (d, 1H).

EXAMPLE 105 Example 4108.1002-007 Example 515(S)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.984,m/z=520.1; ¹H NMR (CDCl₃) 1.52 (d, 3H), 2.11-2.29 (m, 5H), 2.32 (m, 2H),2.81 (s, 3H), 2.83-2.96 (m, 2H), 2.98-3.08 (m, 3H), 3.11-3.22 (m, 2H),5.67 (m, 1H), 7.06 (d, 2H), 7.24-7.36 (m, 5H), 7.38 (d, 2H), 7.61 (s,1H), 7.69 (m, 1H), 8.73 (d, 1H).

EXAMPLE 106 4108.1002-007 Example 517(R)-6-(3-(1,1-dioxo-isothiazolidin-2-yl)propyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(1,1-dioxo-isothiazolidin-2-yl)propyl)-6-phenyl-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.001,m/z=534.1; ¹H NMR (CDCl₃) 1.22-1.33 (m, 1H), 1.52 (d, 3H), 1.68-1.81 (m,1H), 1.83-2.03 (m, 2H), 2.12-2.38 (m, 5H), 2.83-2.91 (m, 5H), 2.93-3.13(m, 5H), 5.68 (m, 1H), 7.09 (d, 2H), 7.18-7.32 (m, 5H), 7.36 (d, 2H),7.61 (s, 1H), 7.68 (s, 1H), 8.24 (s, 1H).

EXAMPLE 107 4108.1002-007 Example 5196-(4-fluorophenyl)-6-methyl-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Isomer 1 of the title compound,(S)-6-(4-fluorophenyl)-6-methyl-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one,was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-methyl-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.28, m/z=405 (M+1);¹H NMR (CDCl₃) 8.84 (d, 1H, J=6.1 Hz), 7.81 (d, 1H, J=5.9 Hz), 7.75 (s,1H), 7.70 (d, 2H, J=8.2 Hz), 7.52 (d, 2H, J=8.20 Hz), 7.34-7.31 (m, 2H),7.09 (t, 2H, J=8.6 Hz), 5.81 (q, 1H, J=7.2 Hz), 2.89 (s, 3H), 2.84-2.72(m, 2H), 2.31 (dt, 1H, J=13.9, 3.7 Hz), 2.11-2.03 (m, 1H), 1.64 (s, 3H),1:38 (d, 3H, J=7 Hz).

Isomer 2 of the title compound,(R)-6-(4-fluorophenyl)-6-methyl-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one,was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-methyl-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.18, m/z=405 (M+1);¹H NMR (CDCl₃) 8.83 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.48 (d, 2H,J=7.3 Hz), 7.32 (br m, 2H), 7.16 (d, 2H, J=6.7), 7.04 (t, 2H, J=7.6 Hz),5.77 (q, 1H, J=6.7 Hz), 3.05 (br m, 1H), 2.89 (s, 3H, 2.42-2.32 (m, 2H),2.23 (br m, 1H), 1.64 (s, 3H), 1.59 (d, 3H, J=6.7 Hz).

EXAMPLE 108 4108.1002-007 Example 542(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyrazin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromopyrazine following a procedure analogous to that described inExample 1 Step 2. LC-MS Method 2 t_(R)=1.157, m/z=458; ¹H NMR (CDCl₃)1.31 (m, 1H), 1.52 (d, 3H), 1.63 (m, 1H), 1.81-1.95 (m, 2H), 2.09-2.32(m, 3H), 2.91 (m, 1H), 3.68 (t, 2H), 5.69 (m, 1H), 6.91 (m, 4H), 7.21(m, 2H), 7.73 (m, 2H), 8.43 (s, 1H), 8.56 (s, 1H), 8.89 (s, 1H).

EXAMPLE 109 4108.1002-007 Example 543(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-5-(trifluoromethyl)pyridine following a procedure analogousto that described in Example 14. LC-MS Method 1 t_(R)=1.86, m/z=503(M+1); ¹H NMR (CDCl₃) 8.87 (s, 1H), 7.93 (dd, 1H), 7.72 (t, 3H), 7.18(m, 2H), 6.98 (m, 4H), 5.67 (m, 1H), 3.52 (t, 1H), 2.89 (m, 1H), 1.49(d, 3H).

EXAMPLE 110 4108.1002-007 Example 5446-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-5-cyanopyridine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.159, m/z=442.4; ¹HNMR (CD₃OD) 1.21 (m, 1H), 1.48 (d, 3H), 1.53 (m, 1H), 1.85 (m, 2H), 2.15(m, 1H), 2.22 (m, 1H), 2.42 (m, 1H), 3.05 (m, 1H), 3.38 (m, 2H), 5.50(m, 1H), 6.98 (d, 2H), 7.25 (m, 3H), 7.28 (m, 2H), 7.79 (d, 2H), 7.89(d, 1H), 8.08 (m, 1H), 8.82 (s, 1H).

EXAMPLE 111 Example 4108.1002-007 Example 5456-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile

The title compound was prepared from(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-5-cyanopyridine following procedures analogous to thosedescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.301, m/z=416; ¹HNMR (CDCl₃) 1.09 (d, 6H), 1.49 (d, 3H), 2.09-2.22 (m, 4H), 2.37 (m, 1H),2.87 (m, 1H), 5.68 (m, 1H), 6.92-7.01 (t, 2H), 7.06 (m, 2H), 7.23 (m,2H), 7.71 (d, 1H), 7.78 (d, 2H), 7.91 (d, 1H), 8.88 (s, 1H). Thecompound was dissolved in refluxing isopropyl acetate and allowed tocool slowly to afford a solid with mp 155-157° C.

EXAMPLE 112 4108.1002-007 Example 546(R)-3-((S)-1-(4-(5-fluoropyridin-2-yl)phenyl)ethyl)-6-(3-hydroxpropyl)-6-Phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-5-fluoropyridine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.197, m/z=435.1; ¹HNMR (CDCl₃) 1.21-1.37 (m, 2H), 1.48 (d, 3H), 1.81-1.95 (m, 2H), 2.18 (m,1H), 2.20-2.31 (m, 2H), 2.85 (m, 1H), 3.52 (t, 2H), 5.65 (m, 1H), 6.95(d, 2H), 7.22 (m, 3H), 7.28 (m, 2H), 7.40 (m, 1H), 7.58 (m, 3H), 8.42(d, 1H).

EXAMPLE 113 4108.1002-007 Example 547(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyrimidin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-chloropyrimidine following procedures analogous to those describedin Example 1 Step 2. LC-MS Method 2 t_(R)=1.401, m/z=436.1; ¹H NMR(CDCl₃) 1.53 (d, 3H), 1.62 (m, 1H), 1.81-1.98 (m, 3H), 2.15 (m, 2H),2.31 (m, 1H), 2.76 (m, 1H), 3.51 (t, 2H), 5.67 (m, 1H), 6.92 (m, 4H),7.11 (m, 1H), 7.19 (m, 1H), 8.15 (d, 2H), 8.71 (d, 2H).

EXAMPLE 114 4108.1002-007 Example 548(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-chloro-6-methylpyridazine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.09, m/z=450; ¹HNMR (CDCl₃) 1.26-1.39 (m, 1H), 1.50 (d, 3H), 1.59-1.70 (m, 1H),1.81-1.99 (m, 3H), 2.09-2.20 (m, 2H), 2.22-2.34 (m, 1H), 2.71 (s, 3H),2.90 (m, 1H), 3.50 (t, 2H), 5.67 (m, 1H), 6.90-7.08 (m, 4H), 7.19 (m,1H), 7.21 (m, 1H), 7.33 (d, 1H), 7.62 (d, 1H), 7.77 (d, 2H).

EXAMPLE 115 4108.1002-007 Example 549(S)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.996,m/z=461.1; ¹H NMR (CDCl₃) 0.35 (m, 1H), 0.17 (m, 3H), 0.51 (m, 1H), 0.61(m, 1H), 1.48 (d, 3H), 2.11 (s, 2H), 2.28 (m, 1H), 2.42 (m, 2H), 2.56(s, 3H), 2.71 (s, 1H), 2.95 (m, 1H), 5.63 (m, 1H), 6.91 (m, 2H), 6.98(m, 2H), 7.19 (m, 1H), 7.26-7.38 (m, 5H), 8.49 (d, 1H).

EXAMPLE 116 4108.1002-007 Example 5503-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

The title compound was prepared from3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrileand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.926,m/z=472.2; ¹H NMR (CD₃OD) 1.31 (s, 3H), 1.41 (s, 1H), 1.58 (d, 3H), 2.30(m, 2H), 2.34 (m, 1H), 2.43 (m, 1H), 2.61 (d, 2H), 2.81 (s, 3H), 3.21(m, 1H), 5.62 (m, 1H), 7.08 (m, 2H), 7.29 (d, 2H), 7.41 (m, 2H), 7.79(d, 2H), 8.09 (m, 1H), 8.19 (s, 1H), 8.68 (d, 1H).

EXAMPLE 117 4108.1002-007 Example 551N-methyl-N-(2-((S)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)methanesulfonamide

The title compound was prepared fromN-(2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)-N-methylmethanesulfonamideand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=0.989,m/z=508.1; ¹H NMR (CDCl₃) 1.53 (d, 3H), 2.17-2.32 (m, 5H), 2.63 (s, 3H),2.71 (s, 3H), 2.81 (s, 3H), 2.93 (m, 2H), 3.22 (m, 1H), 5.67 (m, 1H),7.08 (m, 2H), 7.21 (s, 2H), 7.25 (m, 3H), 7.33 (m, 2H), 7.61 (s, 1H),7.71 (d, 1H), 8.72 (d, 1H).

EXAMPLE 118 4108.1002-007 Example 552(R)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-6-phenyl-6-(2-(1,1-dioxoisothiazolidin-2-yl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-oneand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2.

EXAMPLE 119 Example 4108.1002-007 Example 553N-methyl-N-(3-((R)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide

The title compound was prepared fromN-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylmethanesulfonamideand 2-methylpyridine-4-boronic acid following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1, m/z=522.1;¹H NMR (CDCl₃) 1.23 (m, 1H), 1.48 (d, 3H), 1.68-1.99 (m, 3H), 2.11-2.31(m, 3H), 2.56 (s, 3H), 2.66 (s, 3H), 2.68 (s, 3H), 2.84-3.08 (m, 3H),5.68 (m, 1H), 6.92 (d, 1H), 7.15 (d, 1H), 7.25 (m, 4H), 7.31 (m, 4H),8.43 (d, 1H).

EXAMPLE 120 4108.1002-007 Example 5544-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,6-dimethylpyridine1-oxide

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogousto that described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.086,m/z=461.1; ¹H NMR (CDCl₃) 1.34 (m, 1H), 1.50 (d, 3H), 1.61-1.72 (m, 2H),1.88-2.00 (m, 2H), 2.18 (m, 1H), 2.22-2.34 (m, 2H), 2.62 (s, 6H), 2.88(m, 1H), 3.51 (t, 2H), 5.65 (m, 1H), 6.93 (d, 2H), 7.21 (m, 1H), 7.26(m, 4H), 7.29-7.38 (m, 4H).

EXAMPLE 121 4108.1002-007 Example 5554-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,6-dimethylpyridine1-oxide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogousto that described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.185,m/z=459.1; ¹H NMR (CDCl₃) 1.11 (s, 3H), 1.18 (s, 3H), 1.57 (d, 3H), 2.20(s, 2H), 2.22-2.35 (m, 2H), 2.38-2.49 (m, 1H), 2.72 (s, 6H), 2.91 (m,1H), 5.70 (m, 1H), 7.08 (d, 2H), 7.31 (m, 3H), 7.37 (m, 4H), 7.43 (s,2H).

EXAMPLE 122 4108.1002-007 Example 5564-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)-2,6-dimethylpyridine1-oxide

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogousto that described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.092,m/z=479.1; ¹H NMR (CDCl₃) 1.38 (m, 1H), 1.56 (d, 3H), 1.71 (m, 1H), 1.95(m, 2H), 2.19-2.31 (m, 3H), 2.58 (s, 3H), 2.61 (s, 3H), 2.95 (m, 1H),3.58 (m, 1H), 5.71 (m, 1H), 7.05 (m, 4H), 7.21-7.32 (m, 4H), 7.38 (m,2H).

EXAMPLE 123 4108.1002-007 Example 5574-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)-2,6-dimethylpyridine1-oxide

The title compound was prepared from(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneone and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.354, m/z=493; ¹H NMR (CDCl₃) 1.18 (d, 6H), 1.48 (d, 3H),2.08-2.21 (m, 5H), 2.36 (m, 1H), 2.53 (s, 6H), 2.82 (m, 1H), 5.65 (m,1H), 6.98 (m, 4H), 7.18 (m, 4H), 7.28 (m, 2H).

EXAMPLE 124 4108.1002-007 Example 5584-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)-2-methylpyridine1-oxide

The title compound was prepared from(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-onefollowing a procedure analogous to that described in Example 38. LC-MSMethod 1 t_(R)=1.28, m/z=479 (M+1); ¹H NMR (CDCl₃) 8.52 (d, J=6.2 Hz,1H), 7.56-7.27 (m, 6H), 7.11-7.00 (m, 4H), 5.70 (q, J=7.0 Hz, 1H),2.97-2.93 (m, 1H), 2.69 (s, 3H), 2.50-2.42 (m, 1H), 2.31-2.16 (m, 4H),1.55 (d, J=7.0 Hz, 3H), 1.14 (s, 6H).

EXAMPLE 125 4108.1002-007 Example 559(R)-3-((S)-1-(4-(2-aminopyridin-4-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-amino-4-bromopyridine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=0.951, m/z=432; ¹HNMR (CDCl₃) 1.26-1.40 (m, 1H), 1.48 (d, 3H), 1.59-1.63 (m, 1H),1.83-1.95 (m, 2H), 2.09-2.20 (m, 1H), 2.21-2.37 (m, 2H), 2.86 (m, 1H),3.50 (m, 2H), 4.54-4.75 (s, 2H), 5.62 (m, 1H), 6.56 (s, 1H), 6.71 (d,1H), 6.90 (d, 2H), 7.21-7.33 (m, 7H), 8.00 (m, 1H).

EXAMPLE 126 4108.1002-007 Example 561(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2-methylpyrimidine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.159, m/z=450; ¹HNMR (CDCl₃) 1.33 (m, 3H), 1.52 (m, 3H), 1.63 (m, 3H), 1.80-1.95 (m, 2H),2.15-2.30 (m, 3H), 2.75 (s, 3H), 2.90 (m, 1H), 3.51 (m, 2H), 5.68 (m,1H), 6.99 (m, 4H), 7.20 (m, 2H), 7.41 (m, 1H), 7.79 (d, 2H), 8.60 (m,1H).

EXAMPLE 127 4108.1002-007 Example 562(R)-3-((S)-1-(4-(2,6-dimethylpyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyrimidine following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 tR=1.073, m/z=464.1;¹H NMR (CD₃OD) 1.21 (m, 1H), 1.48 (d, 3H), 1.82 (m, 2H), 2.15 (m, 1H),2.23 (m, 2H), 2.38 (m, 1H), 2.46 (s, 3H), 2.62 (s, 3H), 3.08 (m, 1H),3.39 (m, 2H), 5.51 (m, 1H), 6.95-7.08 (m, 4H), 7.21 (m, 2H), 7.51 (s,1H), 7.83 (d, 2H).

EXAMPLE 128 4108.1002-007 Example 563(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-chloropyrimidine following a procedure analogous to that describedin Example 1 Step 2. LC-MS Method 2 t_(R)=1.172, m/z=392.1; ¹H NMR(CDCl₃) 1.28-1.40 (m, 1H), 1.52 (m, 3H), 1.64 (m, 2H), 1.81-1.99 (m,2H), 2.09-2.37 (m, 3H), 2.90 (m, 1H), 3.51 (t, 2H), 5.68 (m, 1H),6.88-7.07 (m, 3H), 7.16-7.28 (m, 3H), 7.58 (m, 1H), 7.79 (d, 2H),8.61-8.80 (d, 1H), 9.18 (s, 1H).

EXAMPLE 129 4108.1002-007 Example 564(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyrimidin-5-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromopyrimidine following a procedure analogous to that describedin Example 1 Step 2. LC-MS Method 2 t_(R)=1.332, m/z=436.1; ¹H NMR(CD₃OD) 1.49 (d, 3H), 1.83 (m, 2H), 2.14-2.28 (m, 4H), 2.42 (m, 1H),3.08 (m, 1H), 3.49 (m, 2H), 5.52 (m, 1H), 6.99 (t, 2H), 7.08 (d, 2H),7.23 (m, 2H), 7.42 (d, 2H), 8.91 (s, 2H), 9.06 (s, 1H).

EXAMPLE 130 4108.1002-007 Example 569(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(pyrazin-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromopyrazine following a procedure analogous to that described inExample 1 Step 2. LC-MS Method 2 t_(R)=1.249, m/z=374; ¹H NMR (CDCl₃)1.12 (s, 3H), 1.28 (s, 3H), 1.58 (m, 3H), 2.19-2.20 (m, 4H), 2.39 (m,1H), 2.89 (m, 1H), 5.74 (m, 1H), 7.09 (m, 2H), 7.28-7.40 (m, 5H), 7.78(m, 2H), 8.48 (m, 1H), 8.59 (m, 1H), 8.94 (m, 1H).

EXAMPLE 131 4108.1002-007 Example 570(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(pyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-chloropyrimidine following a procedure analogous to that describedin Example 1 Step 2. LC-MS Method 2 t_(R)=1.167, m/z=374; ¹H NMR (CDCl₃)1.06 (s, 3H), 1.11 (s, 3H), 1.49 (d, 3H), 2.11 (s, 1H), 2.17 (s, 2H),2.21 (m, 1H), 2.35 (m, 1H), 2.80 (m, 1H), 5.66 (m, 1H), 7.02 (d, 2H),7.21-7.36 (m, 5H), 7.54 (d, 1H), 7.78 (d, 2H), 8.68 (d, 1H), 9.16 (s,1H).

EXAMPLE 132 4108.1002-007 Example 571(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-chloropyridazine following a procedure analogous to that describedin Example 1 Step 2. LC-MS Method 2 t_(R)=1.067, m/z=436.1; ¹H NMR(CDCl₃) 0.82 (m, 3H), 1.52 (d, 3H), 1.65 (m, 1H), 1.80-1.98 (m, 2H),2.11-2.28 (m, 3H), 2.91 (m, 1H), 3.51 (t, 3H), 5.68 (m, 1H), 6.94-7.04(m, 4H), 7.18 (m, 2H), 7.47 (m, 1H), 7.71 (d, 1H), 7.78 (d, 2H), 9.08(d, 1H).

EXAMPLE 133 4108.1002-007 Example 572(R)-3-((S)-1-(4-(2,6-dimethylpyridin-4-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyridine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.228, m/z=445; ¹HNMR (CDCl₃) 1.32 (m, 1H) 1.51 (d, 3H), 1.60-1.72 (m, 1H), 1.86-2.02 (m,2H), 2.19 (m, 1H), 2.25-2.39 (m, 2H), 2.79 (s, 6H), 2.93 (m, 1H), 3.50(t, 2H), 5.64 (m, 1H), 7.00 (d, 2H), 7.21 (m, 2H), 7.29 (m, 2H), 7.32(m, 3H), 7.40 (m, 2H).

EXAMPLE 134 4108.1002-007 Example 573(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Method 1

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-chloro-6-methylpyridazine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.118, m/z=446; ¹HNMR (CD₃OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.26(m, 1H), 2.50 (m, 2H), 2.69 (s, 3H), 3.08 (m, 1H), 5.59 (m, 1H), 7.11(m, 2H), 7.25-7.40 (5H), 7.63 (m, 1H), 7.82 (m, 2H), 7.98 (d, 1H). Thecompound was dissolved in refluxing methyl acetate and allowed to coolslowly to rt to afford a solid with mp 149.5-151.5° C.

Method 2

(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(6-methyl-pyridazin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-onewas prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 3-chloro-6-methyl-pyridazine following a procedure analogous to thatdescribed in Example 138 Method 2. Yield: 3.09 g (62% of theory). Massspectrum (ESI+): m/z=446 [M+H]⁺.

EXAMPLE 135 4108.1002-007 Example 574(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyrimidin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-chloro-2-methylpyrimidine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.196, m/z=446; ¹HNMR (CD₃OD) 0.92 (s, 3H), 1.27 (s, 3H), 1.58 (d, 3H), 2.12 (s, 2H), 2.23(m, 1H), 2.51-2.66 (m, 2H), 2.70 (s, 3H), 3.07 (m, 1H), 5.59 (m, 1H),7.09 (d, 2H), 7.16-7.42 (m, 5H), 7.65 (d, 1H), 7.89 (d, 2H), 8.61 (d,1H).

EXAMPLE 136 4108.1002-007 Example 575(S)-3-((S)-1-(4-(5-fluoropyridin-2-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-5-fluoropyridine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.363, m/z=390.9; ¹HNMR (CDCl₃) 1.11 (s, 3H), 1.19 (s, 3H), 1.53 (d, 3H), 2.16-2.30 (m, 4H),2.32-2.43 (m, 1H), 2.86 (m, 1H), 5.71 (m, 1H), 7.03 (d, 2H), 7.30 (m,1H), 7.36 (m, 4H), 7.44 (m, 1H), 7.69 (dd, 1H), 7.68 (d, 2H), 8.43 (d,1H). The compound was dissolved in refluxing ethyl acetate and allowedto cool slowly to rt to afford a solid with mp 159-160° C.

EXAMPLE 137 4108.1002-007 Example 576(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyrimidin-5-yl)phenyl)ethyl)-1,3-oxazinan-2-one

Step 1

To a solution of ZnBr₂ (1.33 g, 6 mmol) in THF (15 mL) was added MeMgBr(0.69 g, 6 mmol) under N₂ at −78° C. The mixture was stirred for 1 h andused for next step. To a solution of 5-bromo-2-iodo-pyrimidine (1.42 g,5 mmol) in THF (15 mL) was added Pd(PPh₃)₄ (0.366 g, 0.33 mmol) and theprepared MeZnBr solution (10 mL) under N₂ at 0° C. The mixture washeated to 60° C. for 5 h during which time a second portion of MeZnBrsolution (5 mL) was added. After cooling to room temperature, thereaction was poured into aqueous NH₄Cl solution. The mixture wasextracted with EtOAc. The organic phase was separated and dried overNa₂SO₄, concentrated to give 5-bromo-2-methylpyrimidine (60 mg, 7%). ¹HNMR (CDCl₃): 1.63 (s, 3H), 8.82 (s, 2H).

Step 2

To a solution of(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(61 mg, 0.13 mmol), 5-bromo-2-methylpyrimidine (18 mg, 0.11 mmol),PdCl₂(PPh₃)₂ (6 mg, 10%) and aqueous solution of Cs₂CO₃ (2 mol/L, 0.13mL) in 1,4-dioxane (1 mL) was heated to reflux overnight. The reactionwas quenched with water. The organic layer was separated, dried andconcentrated to give the residue, which was purified by columnchromatography to give(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methylpyrimidin-5-yl)phenyl)ethyl)-1,3-oxazinan-2-one(22 mg, 39%). ¹H NMR (CDCl₃): 1.42 (m, 1H), 1.48 (d, 3H), 1.67 (m, 1H),1.71-1.99 (m, 4H), 2.11-2.41 (m, 3H), 2.52 (s, 3H), 2.72 (m, 1H), 3.53(m, 2H), 5.62 (m, 1H), 6.89-7.04 (m, 4H), 7.15-7.33 (m, 4H), 8.70 (s,2H). LC-MS Method 2 t_(R)=1.184, m/z=450; ¹H NMR (CDCl₃) 1.20 (d, 1H),1.27-1.40 (m, 1H), 1.49 (d, 3H), 1.59-1.70 (m, 1H), 1.71-2.07 (m, 4H),2.11-2.33 (m, 3H), 2.70 (s, 3H), 2.90 (m, 1H), 3.46-3.61 (t, 2H), 5.67(m, 1H), 6.90-7.11 (m, 4H), 7.26 (m, 4H), 8.57-8.83 (s, 2H).

EXAMPLE 138 4108.1002-007 Example 5836-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile

Method 1

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(200 mg, 0.42 mmol) in 1,4-dioxane (1.5 mL) was added6-bromonicotinonitrile (123 mg, 0.67 mmol), Pd(PPh₃)₂Cl₂ (30 mg, 0.042mmol), and Cs₂CO₃ (1 mL, 2 M) were added. The vessel was sealed with aseptum and placed into the microwave cavity. Microwave irradiation of100 W was used, and the temperature being ramped from rt to 120° C. Oncethis temperature was reached, the reaction mixture was held at thistemperature for 30 min. After the mixture was cooled to rt, the mixturewas filtered. The filtrate was extracted with EtOAc (4×20 mL). Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedto give the crude product, which was purified by preparative TLC to give6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile(120 mg, 62%). LC-MS Method 2 t_(R)=1.33, m/z=398; ¹H NMR (CDCl₃): 1.13(s, 3H), 1.19 (s, 3H), 1.58 (d, 3H), 2.22 (m, 2H), 2.27 (m, 2H), 2.40(m, 1H), 2.89 (m, 1H), 3.49 (s, 1H), 5.73 (m, 1H), 7.11 (d, 2H),7.28-7.38 (m, 5H), 7.80 (m, 3H), 8.00 (d, 1H), 8.93 (s, 1H).

Method 2

2 M aqueous Na₂CO₃ solution (1.04 mL) was added to a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.50 g) and 6-chloro-nicotinonitrile (0.22 g) in dimethylformamide (3mL). The resulting mixture was sparged with argon for 5 min, before[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)dichloromethane complex (51 mg) is added. The mixture was heated to 100°C. and stirred at this temperature overnight. After cooling to ambienttemperature, water was added and the resulting mixture was extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried (MgSO₄), and concentrated. The residue was purified bychromatography on silica gel (CH₂Cl₂/MeOH 98:2->80:20) to afford(S)-6-(4-{(S)-1-[6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-nicotinonitrileas an oil (0.50 g) which was crystallized from a mixture of EtOAc (15mL) and iPr₂O (5 mL) by scratching to yield a solid, mp 160-162° C.Yield: 0.32 g (67% of theory). Mass spectrum (ESI⁺): m/z=456 [M+H]⁺.mp=160-162° C.

EXAMPLE 139 4108.1002-007 Example 585(S)-3-((S)-1-(4-(2,6-dimethylpyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyridine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.049, m/z=459.1; ¹HNMR (CD₃OD) 0.94 (s, 3H), 1.24 (s, 3H), 1.55 (d, 3H), 2.15 (s, 2H), 2.23(m, 1H), 2.45 (m, 1H), 2.51 (s, 6H), 3.05 (m, 1H), 5.57 (m, 1H), 7.04(d, 2H), 7.24 (s, 2H), 7.26-7.38 (m, 5H), 7.45 (m, 1H).

EXAMPLE 140 4108.1002-007 Example 5876-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide

6-(4-((S)-1-((R)-6-(3-hydroxypropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile(50 mg, 0.11 mmol) and H₂O₂ (0.04 mL, 30%), K₂CO₃ (6.27 mg, 0.046 mmol)in DMSO (0.39 mL) was stirred overnight at room temperature. Thereaction was added water and EtOAc. The layer was separated. The organicphase was washed with brine and dried, concentrated to give the product(9.95 mg, 19%) LC-MS Method 2 t_(R)=1.083, m/z=460.1; ¹H NMR (CD₃OD)1.21 (m, 1H), 1.51 (d, 3H), 1.53-1.64 (m, 1H), 1.85-1.94 (m, 2H),2.10-2.21 (m, 1H), 2.29 (m, 1H), 2.42 (m, 1H), 3.03 (m, 1H), 3.39 (t,2H), 5.52 (m, 1H), 6.99 (d, 2H), 7.21-7.34 (m, 5H), 7.22 (d, 2H), 7.31(d, 1H), 8.22 (d, 1H), 8.98 (s, 1H).

EXAMPLE 141 4108.1002-007 Example 589(R)-3-((S)-1-(4-(2,6-dimethylpyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-bromo-2,6-dimethylpyridine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.012, m/z=463.1; ¹HNMR (CDCl₃) 1.32 (m, 2H), 1.49 (d, 3H), 1.62 (m, 2H), 1.86-1.96 (m, 2H),2.17-2.29 (m, 3H), 2.31 (s, 3H), 2.49 (s, 3H), 2.93 (m, 1H), 3.51 (m,2H), 5.68 (m, 1H), 6.88-7.03 (m, 7H), 7.25 (m, 3H).

EXAMPLE 142 4108.1002-007 Example 5973-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(2-methylpyrimidin-4-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

The title compound was prepared from3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrileand 4-chloro-2-methylpyrimidine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 1 t_(R)=1.55, m/z=473 (M+1);¹H NMR (CDCl₃) 8.96 (s, 1H), 7.98 (d, 2H), 7.84 (s, 1H), 7.29 (m, 2H),7.10 (m, 4H), 5.72 (d, 1H), 3.05 (d, 1H), 2.97 (s, 3H), 2.91 (m, 1H),2.51 (d, 1H), 1.61 (d, 3H), 1.38 (d, 3H), 1.27 (d, 3H).

EXAMPLE 143 4108.1002-007 Example 5986-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide

To a solution of6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile(120 mg, 0.26 mmol) in DMSO (8 mL) were added H₂O₂ (0.5 mL, 30%) andK₂CO₃ (35 mg, 0.26 mmol), and the mixture was stirred at rt for 3 h. Thereaction was quenched with H₂O (10 mL) and the mixture was extractedwith EtOAc (4×20 mL). The organic layer was washed with brine, driedover Na₂SO₄ and concentrated to give the crude product, which waspurified by preparative HPLC to give6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide(55.46 mg, 45%). LC-MS Method 2 t_(R)=1.12 min, m/z=474, 416. ¹H NMR(CDCl₃): 1.03 (s, 3H), 1.09 (s, 3H), 1.46 (d, 3H), 2.13-2.26 (m, 5H),2.30 (m, 1H), 2.44 (s, 1H), 2.79 (d, 1H), 5.61 (m, 1H), 6.15-6.38 (s,1H), 6.97 (d, 2H), 7.13-7.29 (m, 5H), 7.60 (d, 2H), 7.70 (d, 2H), 8.15(d, 1H), 9.05 (s, 1H).

EXAMPLE 144 4108.1002-007 Example 599(S)-3-((S)-1-(4-(2,6-dimethylpyridin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one

The title compound was prepared(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyridine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.001, m/z=477.1; ¹HNMR (CDCl₃) 1.05-1.23 (d, 6H), 1.49 (d, 3H), 2.10-2.23 (m, 4H),2.31-2.42 (m, 1H), 2.56 (s, 6H), 2.89 (m, 1H), 5.67 (m, 1H), 6.92-7.07(m, 4H), 7.08 (s, 2H), 7.22 (m, 2H), 7.33 (d, 2H).

EXAMPLE 145 4108.1002-007 Example 6046-(4-((S)-1-((R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile

The title compound was prepared fromN′-acetyl-3-((R)-3-((S)-1-(4-(5-cyanopyridin-2-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazidefollowing procedures analogous to those described in Example 12 Step 6.LC-MS Method 2 t_(R)=1.265, m/z=494.1; ¹H NMR (CDCl₃) 1.59 (d, 3H), 2.06(m, 1H), 2.33 (m, 5H), 2.48 (s, 2H), 2.52-2.71 (m, 2H), 2.97 (m, 1H),3.09 (m, 1H), 5.72 (m, 1H), 7.08 (d, 2H), 7.29 (m, 2H), 7.32 (m, 2H),7.34-7.58 (m, 2H), 7.77 (m, 2H), 7.99 (d, 1H), 8.89 (s, 1H).

EXAMPLE 146 4108.1002-007 Example 6076-(4-((S)-1-((R)-6-(2-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile

The title compound was prepared fromN′-acetyl-3-((R)-3-((S)-1-(4-(5-cyanopyridin-2-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazidefollowing a procedure analogous to that described in Example 39 Step 4.LC-MS Method 2 t_(R)=1.306, m/z=511.1; ¹H NMR (CDCl₃) 1.59 (d, 3H), 2.25(m, 1H), 2.43 (m, 2H), 2.49 (m, 2H), 2.74 (s, 3H), 2.82 (m, 1H), 2.99(m, 1H), 3.31 (m, 1H), 5.72 (m, 1H), 7.09 (d, 2H), 7.31 (m, 3H), 7.40(m, 2H), 7.72-7.87 (m, 3H), 8.00 (d, 1H), 8.91 (s, 1H).

EXAMPLE 147 4108.1002-007 Example 609(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 2-methoxypyridin-4-ylboronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.9 min, m/z=447(M+1); ¹H NMR (CDCl₃) 8.29 (1H, d, J=5.5 Hz), 7.34 (2H, m), 7.21-7.15(m, 3H), 7.02-6.93 (5H, m), 5.67-5.61 (1H, m), 4.05 (3H, s), 3.53 (1H,t, J=6.41 Hz), 2.97-2.93 (1H, m), 2.33-2.11 (3H, m), 2.06-1.83 (3H, m),1.67-1.57 (1H, m), 1.50 (3H, d, J=7.03), 1.36-1.26 (1H, m).

EXAMPLE 148 4108.1002-007 Example 610(R)-6-(4-fluorophenyl)-3-((S)-1-(4-(5-fluoropyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-oneand 5-fluoropyridin-3-ylboronic acid following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.5 min, m/z=453(M+1).

EXAMPLE 149 4108.1002-007 Example 619(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methylpyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

Method 1

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-methyl-5-bromopyrimidine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.221 min,m/z=468.2; ¹H NMR (CDCl₃) 1.06 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H),2.11-2.28 (m, 4H), 2.31-2.42 (m, 1H), 2.70 (s, 3H), 2.82 (m, 1H), 5.65(m, 1H), 7.00 (d, 2H), 7.21-7.34 (m, 7H), 8.19 (s, 2H).

Method 2

Step 1.5-Bromo-2-(5-bromo-2-methyl-1,4-dihydro-pyrimidin-4-ylmethyl)-pyrimidine

5-Bromo-2-methyl-pyrimidine-4-carboxylic acid (5.0 g) was heated aboveits melting point (m_(p) 176° C.) during which decarboxylation takesplace. After cooling to ambient temperature, the tar-like substance waspurified by chromatography on silica gel (CH₂Cl₂/MeOH 90:10->70:30) toafford the title compound as a black liquid. Yield: 0.45 g (6% oftheory). Mass spectrum (ESI⁺): m/z=345/347/349 (2 Br) [M+H]⁺

Step 2.(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(2-methyl-pyrimidin-5-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

2 M aqueous Na₂CO₃ solution (1.67 mL) was added to a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.80 g) and5-bromo-2-(5-bromo-2-methyl-1,4-dihydro-pyrimidin-4-ylmethyl)-pyrimidine(0.40 g) in dimethylformamide (5 mL). The resulting mixture was spargedwith argon for 5 min, before[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)dichloromethane complex (82 mg) was added. The mixture was heated to100° C. and stirred at this temperature overnight. After cooling toambient temperature, water was added, and the resulting mixture wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried (MgSO₄), and concentrated. The residue was purified bychromatography on silica gel (CH₂Cl₂/MeOH 95:5->80:20) followed by HPLC(MeCN/H₂O/NH₄OH) to afford the title compound (340 mg) which wascrystallized from 1:3 EtOAc/diisopropylether by scratching to yield asolid, mp 112-115° C. Yield: 0.25 g (34% of theory). Mass spectrum(ESI⁺): m/z=446 [M+H]⁺

EXAMPLE 150 4108.1002-007 Example 6276-(4-{1-[6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-N-methyl-nicotinamide

Step 1

To a solution of(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(6.6 g, 15.2 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.1 g, 24.3mmol) in dry DMSO (20 mL) was added KOAc (4.8 g, 48.6 mmol) andPd(dppf)Cl₂ (372 mg, 0.46 mmol). After addition, the mixture was warmedto 100° C. for 20 h. After TLC showed the starting material haddisappeared, the solid was filtered off. Water (60 mL) and EtOAc (20 mL)were added, the layers were separated and the aqueous layer wasextracted with EtOAc (3×15 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to give(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(4.4 g, 60%), which was purified by column. ¹H NMR (CDCl₃): 1.03 (s,3H), 1.12 (s, 3H), 1.22 (s, 12H), 1.49 (d, 3H), 2.13 (m, 4H), 2.26 (m,1H), 2.73 (m, 1H), 5.64 (q, 1H), 6.91 (d, 2H), 7.38 (m, 5H), 7.51 (d,2H).

Step 2

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(500 mg, 1.04 mmol) and methyl 6-bromonicotinate (292 mg, 1.35 mmol) indry 1,4-dioxane (5 mL) was added CsCO₃ (1 mL, 2 mmol) and Pd(PPh₃)₂Cl₂(50 mg). After addition, the mixture was warmed to 110° C. for 30 minunder microwave. After TLC showed the starting material had disappeared,the solid was filtered off. Water (20 mL) and EtOAc (10 mL) was added,the layers were separated and the aqueous layer was extracted with EtOAc(3×10 mL). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated to give methyl6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate(507 mg, 89%), which was purified by preparative TLC. ¹H NMR (CDCl₃):1.13 (s, 3H), 1.19 (s, 3H), 1.61 (d, 3H), 2.24 (m, 4H), 2.37 (m, 1H),2.88 (m, 1H), 4.02 (s, 3H), 5.76 (q, 1H), 7.11 (d, 2H), 7.29-7.47 (m,6H), 7.78 (m, 1H), 7.82 (m, 2H), 8.38 (d, 1H), 9.31 (s, 1H).

Step 3

Methyl6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate(150 mg, 0.307 mmol) was dissolved in NH₂Me/MeOH (10 mL). The mixturewas stirred at rt overnight. The solvent was removed in vacuo to givethe crude product, which was purified by preparative HPLC and chiralHPLC to afford6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-methylnicotinamide(54 mg, 36%). LC-MS Method 2 t_(R)=1.117 min, m/z=430.1; ¹H NMR (CD₃OD)0.93 (s, 3H), 1.27 (s, 3H), 1.59 (d, 3H), 2.16 (s, 2H), 2.22-2.37 (m,1H), 2.41-2.60 (m, 2H), 2.99 (s, 3H), 3.11 (m, 1H), 5.60 (m, 1H), 7.12(d, 1H), 7.29 (m, 5H), 7.80 (m, 2H), 8.01 (d, 1H), 8.41 (d, 1H), 9.03(s, 1H).

EXAMPLE 151 4108.1002-007 Example 629(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-methylpyrazin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromo-5-methylpyrazine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.257 min, m/z=388;¹H NMR (CDCl₃) 1.07 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.01-2.13 (m,4H), 2.28-2.39 (m, 1H), 2.57 (s, 3H), 2.80 (m, 1H), 5.68 (m, 1H), 7.02(d, 2H), 7.21-7.33 (m, 5H), 7.67 (d, 2H), 8.41 (s, 1H), 8.76 (s, 1H).

EXAMPLE 152 4108.1002-007 Example 6315-fluoro-2-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridine1-oxide

The title compound was prepared from(S)-3-((S)-1-(4-(5-fluoropyridin-2-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-onefollowing a procedure analogous to that described in Example 38. LC-MSMethod 1 t_(R)=1.29 min, m/z=465 (M+1), 407; ¹H NMR (CD₃OD) 8.37 (m,1H), 7.50-7.37 (m, 4H), 7.29-7.19 (m, 5H), 6.97 (d, J=7.9 Hz, 2H), 5.48(q, J=7.0 Hz, 1H), 2.99-2.94 (m, 1H), 2.46-2.33 (m, 2H), 2.22-2.14 (m,1H), 2.06 (s, 2H), 1.46 (d, J=7.0 Hz, 3H), 1.16 (s, 3H), 0.85 (s, 3H).

EXAMPLE 153 4108.1002-007 Example 6325-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrazine-2-carbonitrile

The title compound was prepared from(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-chloropyrazine-2-carbonitrile following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.64 min, m/z=497(M+Na); ¹H NMR (CDCl₃) 8.98 (d, 2H), 7.89 (d, 2H), 7.27 (m, 1H), 7.17(m, 2H), 7.04 (m, 3H), 5.72 (q, 1H), 4.40 (br s, 1H), 2.98 (m, 1H), 1.59(d, 3H), 1.13 (d, 6H).

EXAMPLE 154 4108.1002-007 Example 6334-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)propyl)phenyl)-2,6-dimethylpyridine1-oxide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-oneand 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogousto that described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.185 min,m/z=489.2; ¹H NMR (CDCl₃) 0.96 (t, 3H), 1.03 (s, 3H), 1.12 (s, 3H),1.81-2.00 (m, 4H), 2.11-2.22 (m, 5H), 2.30-2.42 (m, 1H), 2.57 (s, 6H),2.87 (m, 1H), 5.43 (m, 1H), 7.09 (d, 2H), 7.18 (m, 1H), 7.22 (m, 4H),7.26 (m, 2H), 7.31 (m, 2H).

EXAMPLE 155 4108.1002-007 Example 634(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-chloro-6-methylpyridazine following a procedure analogous to thatdescribed in Example 1 Step 2. LC-MS Method 2 t_(R)=1.163 min, m/z=464;¹H NMR (CDCl₃) 1.12 (d, 6H), 1.55 (d, 3H), 2.18 (s, 2H), 2.19-2.28 (m,2H), 2.40 (m, 1H), 2.74 (s, 3H), 2.90 (m, 1H), 5.71 (m, 1H), 6.96-7.05(t, 2H), 7.10 (d, 2H), 7.29 (m, 2H), 7.38 (d, 2H), 7.69 (d, 1H), 7.82(d, 2H).

EXAMPLE 156 4108.1002-007 Example 6356-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N,N-dimethylnicotinamide

The title compound was prepared from methyl6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinateand dimethylamine following a procedure analogous to that described inExample 150 Step 3. LC-MS Method 2 t_(R)=1.708 min, m/z=444.1; ¹H NMR(CDCl₃) 1.10 (s, 3H), 1.18 (s, 3H), 1.56 (d, 3H), 2.18-2.31 (m, 4H),2.32-2.53 (m, 1H), 2.86 (m, 1H), 3.08 (s, 3H), 3.13 (s, 3H), 5.71 (m,1H), 7.08 (d, 2H), 7.29-7.52 (m, 5H), 7.69 (d, 1H), 7.76 (d, 1H), 7.82(d, 1H), 8.70 (s, 1H).

EXAMPLE 157 4108.1002-007 Example 6406-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrazine-2-carbonitrile

The title compound was prepared from(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 6-chloropyrazine-2-carbonitrile following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.61 min, m/z=497(M+Na); ¹H NMR (CDCl3) 8.98 (d, 2H), 7.87 (d, 2H), 7.26 (m, 1H), 7.18(m, 3H), 7.04 (t, 2H), 5.72 (q, 1H), 2.99 (m, 1H), 1.59 (d, 3H), 1.14(d, 6H).

EXAMPLE 158 4108.1002-007 Example 6442-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N,N-dimethylthiazole-5-carboxamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-oneand 2-bromo-N,N-dimethylthiazole-5-carboxamide following a procedureanalogous to that described in Example 1 Step 2. LC-MS Method 2t_(R)=1.215 min, m/z=450.1; ¹H NMR (CD₃OD) 0.92 (s, 3H), 1.22 (s, 3H),1.53 (d, 3H), 2.11 (s, 2H), 2.19-2.28 (m, 1H), 2.40-2.58 (m, 2H),3.00-3.31 (m, 4H), 5.56 (m, 1H), 7.02 (d, 2H), 7.26-7.39 (m, 5H), 7.69(d, 2H), 8.08 (s, 1H). The compound was dissolved in refluxing isopropylacetate and allowed to cool slowly to rt to afford a solid with mp110-111.5° C.

EXAMPLE 159 4108.1002-007 Example 6456-(4-{1-[6-(4-Fluoro-phenyl)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyrazine-2-carboxylicacid amide

The title compound was prepared from6-(4-((S)-1-((S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrazine-2-carbonitrilefollowing a procedure analogous to that described in Example 140. LC-MSMethod 1 t_(R)=1.32 min, m/z=493; ¹H NMR (CDCl₃) 9.24 (d, 2H), 7.88 (s,1H), 7.83 (d, 2H), 4.29 (m, 2H), 7.16 (d, 2H), 7.06 (t, 2H), 6.62 (s,1H), 5.74 (q, 1H), 3.00 (m, 1H), 2.48 (m, 1H), 1.60 (d, 3H), 1.17 (d,6H).

EXAMPLE 160 4108.1002-007 Example 656(S)-3-((S)-1-(4-(6-ethoxy-5-methylpyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromo-2-ethoxy-3-methylpyridine following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.314 min,m/z=489; ¹H NMR (CDCl₃) 1.04 (s, 3H), 1.11 (s, 3H), 1.34 (t, 3H), 1.47(d, 3H), 2.13-2.24 (m, 7H), 2.32 (m, 1H), 2.81 (m, 1H), 4.34 (q, 2H),5.62 (q, 1H), 6.93 (d, 2H), 7.17-7.27 (m, 7H), 7.42 (s, 1H), 8.02 (s,1H).

EXAMPLE 161 4108.1002-007 Example 657N-cyclopropyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 6-bromo-N-cyclopropylnicotinamide following a procedure analogous tothat described in Example 14. LC-MS Method 1 t_(R)=1.74 min, m/z=456.1;¹H NMR (CDCl₃) 0.61 (m, 2H), 0.82 (m, 2H), 1.13 (s, 3H), 1.22 (s, 3H),1.49 (d, 3H), 2.17 (m, 3H), 2.21 (m, 1H), 2.31 (m, 1H), 2.79 (m, 1H),2.88 (m, 1H), 5.66 (m, 1H), 6.40 (s, 1H), 6.99 (d, 1H), 7.20-7.31 (m,5H), 7.60 (d, 1H), 7.68 (d, 2H), 8.07 (d, 1H), 8.89 (s, 1H). Thecompound was dissolved in refluxing isopropyl acetate and allowed tocool slowly to it to afford a solid with mp 191-194° C.

6-bromo-N-cyclopropylnicotinamide was prepared from 6-bromonicotinoylchloride and cyclopropylamine.

EXAMPLE 162 4108.1002-007 Example 660(S)-3-((S)-1-(4-(2-ethoxy-6-methylpyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 4-bromo-2-ethoxy-6-methylpyridine following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.259 min,m/z=489.2; ¹H NMR (CDCl₃) 1.10 (s, 3H), 1.15 (s, 3H), 1.34 (m, 3H), 1.49(m, 3H), 2.16 (m, 3H), 2.19 (m, 1H), 2.32 (m, 1H), 2.42 (m, 3H), 2.79(m, 1H), 4.32 (m, 2H), 5.66 (m, 1H), 6.55 (s, 1H), 6.76 (s, 1H), 6.98(m, 2H), 7.19-7.29 (m, 7H).

EXAMPLE 163 4108.1002-007 Example 661N-tert-butyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinamide

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 6-bromo-N-tert-butylnicotinamide following a procedure analogous tothat described in Example 1 Step 2. LC-MS Method 2 t_(R)=1.898 min,m/z=472.2; ¹H NMR (CDCl₃) 1.08 (s, 3H), 1.15 (s, 3H), 1.34 (s, 9H), 1.49(d, 3H), 2.16 (m, 3H), 2.19 (m, 1H), 2.32 (m, 1H), 2.42 (m, 3H), 2.79(m, 1H), 4.32 (m, 2H), 5.66 (m, 1H), 6.55 (s, 1H), 6.76 (s, 1H), 6.98(m, 2H), 7.19-7.29 (m, 7H).

6-bromo-N-tert-butylnicotinamide was prepared from 6-bromonicotinoylchloride and tert-butylamine.

EXAMPLE 164 4108.1002-007 Example 6622-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)isonicotinonitrile

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromoisonicotinonitrile following a procedure analogous to thatdescribed in Example 138 Method 1. LC-MS Method 2 t_(R)=1.419 min,m/z=478.1; ¹H NMR (CD₃OD) 0.93 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.17(s, 2H), 2.25 (m, 1H), 2.41-2.58 (m, 2H), 3.06 (m, 1H), 5.58 (m, 1H),7.08 (d, 2H), 7.25-7.40 (m, 5H), 7.59 (d, 1H), 7.80 (d, 2H), 8.10 (s,1H), 8.29 (d, 1H).

EXAMPLE 165 4108.1002-007 Example 6632-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 2-bromonicotinonitrile following a procedure analogous to thatdescribed in Example 138 Method 1. LC-MS Method 2 t_(R)=1.23 min,m/z=398.1; ¹H NMR (CD₃OD) 0.93 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.17(s, 2H), 2.28 (m, 1H), 2.50 (m, 2H), 3.09 (m, 1H), 5.58 (m, 1H), 7.08(d, 2H), 7.22-7.41 (m, 5H), 7.50 (m, 1H), 7.62 (d, 2H), 8.23 (d, 1H),8.81 (m, 1H). Mass spectrum (ESI⁻): m/z=500 [M+HCOO]⁻

EXAMPLE 166 4108.1002-007 Example 6652,2-dimethyl-3-((R)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

The title compound was prepared from2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrileand 3-chloro-6-methylpyridazine following a procedure analogous to thatdescribed in Example 14. LC-MS Method 1 t_(R)=1.41 min, m/z=455; ¹H NMR(CDCl₃) 8.20 (d, 1H), 7.92 (d, 1H), 7.74 (d, 2H), 7.37 (dt, 6H), 7.05(d, 2H), 5.66 (q, 1H), 3.00 (dm, 1H), 2.93 (s, 3H), 2.49 (m, 2H), 2.34(m, 1H), 2.17 (d, 2H), 1.58 (d, 3H), 1.39 (s, 3H), 1.33 (s, 3H).

EXAMPLE 167 4108.1002-007 Example 677(R)-6-(methoxymethyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-(methoxymethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 3-chloro-6-methylpyridazine following a procedure analogous to thatdescribed in Example 14. Mass spectrum (ESI⁺): m/z=418 [M+H]⁺.

EXAMPLE 168 4108.1002-007 Example 6805-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid ethylamide

2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(75 mg) was added to a solution of5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridine-2-carboxylicacid (0.10 g) and diisopropylethylamine (50 μL) in dimethylformamide (1mL) at room temperature. The resulting solution was stirred for 25 min,before ethylamine (70% in water, 50 μL) was added. The solution wasstirred at room temperature overnight and then concentrated underreduced pressure. The crude product was purified by HPLC on reversedphase (MeCN/H₂O) to afford the title compound as a foam-like solid.Yield: 25 mg (24% of theory). Mass spectrum (ESI⁺): m/z=502 [M+H]⁺

Intermediate XXVII5-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid

2 M aqueous Na₂CO₃ solution (1.3 mL) was added to a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one(0.60 g) and 5-bromo-pyridine-2-carboxylic acid methyl ester (0.41 g) indimethylformamide (4 mL). The resulting mixture was sparged with argonfor 10 min, before[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (61 mg) was added. The mixture was heated to100° C. and stirred at this temperature overnight. After cooling toambient temperature, the mixture was diluted with ethyl acetate andextracted with water and brine. The aqueous extracts were combined,acidified (pH ca. 5-6) using citric acid, and extracted with CH₂Cl₂/MeOH(ca. 10:1). The combined organic extracts were washed with brine anddried (MgSO₄). The solvent was removed and the residue was purified bychromatography on silica gel (CH₂Cl₂/MeOH 98:2->50:50) to afford thetitle compound as a resin-like solid. Yield: 0.44 g (73% of theory);Mass spectrum (ESI⁺): m/z=475 [M+H]⁺.

EXAMPLE 1695-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid methylamide

The title compound was prepared from5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid and methylamine following a procedure analogous to that describedin Example 168. Mass spectrum (ESI⁺): m/z=488 [M+H]⁺.

EXAMPLE 170(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid dimethylamide

The title compound was prepared from5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid and dimethylamine following a procedure analogous to that describedin Example 168. Mass spectrum (ESI⁺): m/z=502 [M+H]⁺.

EXAMPLE 171(S)-6-(2-Hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-thiazol-5-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one

2 M aqueous Na₂CO₃ solution (0.63 mL) was added to a solution of5-bromo-thiazole (70 μL) and(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.30 g) in dimethylformamide (3 mL). The resulting mixture was spargedwith argon for 10 min, before[1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II)dichloromethane complex (15 mg) was added. The mixture was heated to 90°C. and stirred at this temperature for 2 h. After cooling to ambienttemperature, water was added, and the resulting mixture was extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried (MgSO₄), and concentrated. The residue was purified bychromatography on silica gel (cyclohexane/ethyl acetate 50:50->0:100) toafford the title compound as a solid. Yield: 0.19 g (70% of theory);Mass spectrum (ESI⁺): m/z=437 [M+H]⁺.

EXAMPLE 172(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(5-methyl-[1,3,4]thiadiazol-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-5-methyl-[1,3,4]thiadiazole following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁻): m/z=496[M+HCOO]⁻.

EXAMPLE 173(S)-6-(2-Hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-[1,3,4]thiadiazol-2-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-[1,3,4]thiadiazole following a procedure analogous to thatdescribed in Example 171. Mass spectrum (ESI⁺): m/z=438 [M+H]⁺.

EXAMPLE 174(S)-6-(2-Hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-thiazol-2-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-thiazole following a procedure analogous to that describedin Example 171. Mass spectrum (ESI⁺): m/z=437 [M+H]⁺.

EXAMPLE 175(S)-6-(2-Hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-thiazol-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-thiazole following a procedure analogous to that describedin Example 171. Mass spectrum (ESI⁺): m/z=437 [M+H]⁺.

EXAMPLE 1763-{(S)-1-[4-(2,4-Dimethyl-thiazol-5-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 5-bromo-2,4-dimethyl-thiazole following a procedure analogous tothat described in Example 171. Mass spectrum (ESI⁺): m/z=465 [M+H]⁺.

EXAMPLE 177(S)-6-(2-Hydroxy-2-methyl-propyl)-6-phenyl-3-{(S)-1-[4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-1,3,5-trimethyl-1H-pyrazole following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=462 [M+H]⁺.

EXAMPLE 178(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-1-methyl-1H-pyrazole following a procedure analogous to thatdescribed in Example 171. Mass spectrum (ESI⁺): m/z=434 [M+H]⁺.

EXAMPLE 179(S)-6-(2-Hydroxy-2-methyl-propyl)-6-phenyl-3-{(S)-1-[4-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole following a procedureanalogous to that described in Example 171. Mass spectrum (ESI⁻):m/z=550 [M+HCOO]⁻.

EXAMPLE 180(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[(2-methyl-4-thiazol-5-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

A flask charged with a stir bar,3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one(0.30 g), 2-methyl-thiazole (0.15 g), potassium acetate (0.15 g),palladium(II) acetate (5 mg), and N,N-dimethylacetamide (5 mL) wassparged with argon for 10 min. Then, the mixture was heated to 150° C.and stirred at this temperature overnight. After cooling to ambienttemperature, ethyl acetate was added and the resulting mixture waswashed with water and brine. Then, the organic phase was dried (Na₂SO₄)and concentrated. The residue was purified by chromatography on silicagel (cyclohexane/ethyl acetate 80:20->0:100) to afford the titlecompound. Yield: 95 mg (28% of theory); Mass spectrum (ESI⁺): m/z=451[M+H]⁺.

EXAMPLE 181(S)-3-{1-[4-(4,5-Dimethyl-thiazol-2-yl)-phenyl]-ethyl}-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-oneand 4,5-dimethyl-thiazole following a procedure analogous to thatdescribed in Example 180. Mass spectrum (ESI⁺): m/z=465 [M+H]⁺.

EXAMPLE 182(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(6-methanesulfinyl-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 5-bromo-2-methanesulfinyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=493 [M+H]⁺.

5-Bromo-2-methanesulfinyl-pyridine

NalO₄ (0.52 g) dissolved in water (0.5 mL) was added to a solution of5-bromo-2-methylsulfanyl-pyridine (0.25 g) in acetic acid (3 mL) at roomtemperature. The resulting mixture was stirred at room temperatureovernight. Then, water and ethyl acetate were added and the mixture wasstirred for another 10 min. The organic phase was separated and washedwith 10% aqueous Na₂S₂O₃ solution, 10% aqueous K₂CO₃ solution, andbrine. After drying (MgSO₄), the solvent was evaporated to afford thetitle compound. Yield: 0.20 g (72% of theory); Mass spectrum (ESI⁺):m/z=220/222 (Br) [M+H]⁺.

EXAMPLE 183(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(6-methanesulfonyl-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 5-bromo-2-methanesulfonyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=509 [M+H]⁺.

EXAMPLE 184(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(4-methanesulfinyl-pyridin-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-4-methanesulfinyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=493 [M+H]⁺.

2-Bromo-4-methylsulfanyl-pyridine

NaSCH₃ (0.14 g) was added to a solution of 2-bromo-4-iodo-pyridine (0.50g) in dimethylformamide (5 mL) at room temperature. The solution washeated to 60° C. and stirred at this temperature for 4 h. After coolingto room temperature, ethyl acetate was added and the resulting solutionwas washed with water and brine. The organic phase was dried (MgSO₄) andthe solvent was evaporated. The residue was purified by chromatographyon silica gel (cyclohexane/ethyl acetate 98:2->80:20) to afford thetitle compound. Yield: 0.34 g (94% of theory); Mass spectrum (ESI⁺):m/z=204/206 (Br) [M+H]⁺.

2-Bromo-4-methanesulfinyl-pyridine

The title compound was prepared from 2-bromo-4-methylsulfanyl-pyridinefollowing a procedure analogous to that described for5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI⁺):m/z=220/222 (Br) [M+H]⁺.

EXAMPLE 185(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(4-methanesulfonyl-pyridin-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-4-methanesulfonyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=509 [M+H]⁺.

2-Bromo-4-methanesulfonyl-pyridine

3-Chloroperoxybenzoic acid (70%, 0.72 g) was added to a solution of2-bromo-4-methylsulfanyl-pyridine (0.20 g) in dichloromethane (2 mL) atroom temperature. The resulting mixture was stirred at room temperatureovernight. Then, the solution was diluted with dichloromethane and themixture was washed with aqueous K₂CO₃ solution, aqueous Na₂S₂O₃solution, aqueous K₂CO₃ solution again, and brine. After drying (MgSO₄)and removing the solvent, the residue was purified by HPLC on reversedphase (methanol/water) to afford the title compound. Yield: 0.12 g (52%of theory); Mass spectrum (ESI⁺): m/z=236/238 (Br) [M+H]⁺.

EXAMPLE 186(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(5-methanesulfonyl-pyridin-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-5-methanesulfonyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=509 [M+H]⁺.

EXAMPLE 187(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(2-methanesulfonyl-pyridin-4-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-iodo-2-methanesulfonyl-pyridine following a procedure analogous tothat described in Example 171. Mass spectrum (ESI⁺): m/z=509 [M+H]⁺.

4-Iodo-2-methylsulfanyl-pyridine

The title compound was prepared from 2-fluoro-4-iodo-pyridine followinga procedure analogous to that described for2-bromo-4-methylsulfanyl-pyridine in Example 184. Mass spectrum (ESI⁺):m/z=252 [M+H]⁺.

4-Iodo-2-methanesulfonyl-pyridine

The title compound was prepared from 4-iodo-2-methylsulfanyl-pyridinefollowing a procedure analogous to that described for2-bromo-4-methanesulfonyl-pyridine in Example 185. Mass spectrum (ESI⁺):m/z=284 [M+H]⁺.

EXAMPLE 188(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(5-methanesulfonyl-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 3-bromo-5-methanesulfonyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=509 [M+H]⁺.

EXAMPLE 189(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(5-methanesulfinyl-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 3-bromo-5-methanesulfinyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=493 [M+H]⁺.

3-Bromo-5-methanesulfinyl-pyridine

The title compound was prepared from 3-bromo-5-methylsulfanyl-pyridinefollowing a procedure analogous to that described for5-bromo-2-methanesulfinyl-pyridine in Example 182.

EXAMPLE 190(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(6-methanesulfonyl-pyridin-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-6-methanesulfonyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=526[M+NH₄]⁺.

2-Bromo-6-methanesulfonyl-pyridine

The title compound was prepared from 2-bromo-6-methylsulfanyl-pyridinefollowing a procedure analogous to that described for2-bromo-4-methanesulfonyl-pyridine in Example 185. Mass spectrum (ESI⁺):m/z=236/238 (Br) [M+H]⁺.

EXAMPLE 191(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(6-methanesulfinyl-pyridin-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-6-methanesulfinyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=493 [M+H]⁺.

2-Bromo-6-methanesulfinyl-pyridine

The title compound was prepared from 2-bromo-6-methylsulfanyl-pyridinefollowing a procedure analogous to that described for5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI⁺):m/z=220/222 (Br) [M+H]⁺.

EXAMPLE 1923-{(S)-1-[4-(2-Cyclopropyl-pyrimidin-5-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 5-bromo-2-cyclopropyl-pyrimidine (for preparation see WO 2006004532)following a procedure analogous to that described in Example 171. Massspectrum (ESI⁺): m/z=472 [M+H]⁺.

EXAMPLE 1933-{(S)-1-[4-(1,3-Dimethyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 4-bromo-1,3-dimethyl-1H-pyrazole following a procedure analogous tothat described in Example 171. Mass spectrum (ESI⁺): m/z=448 [M+H]⁺.

EXAMPLE 1942-[5-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridin-2-yl]-2-methyl-propionitrile

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-(5-bromo-pyridin-2-yl)-2-methyl-propionitrile following aprocedure analogous to that described in Example 171. Mass spectrum(ESI⁺): m/z=498 [M+H]⁺.

2-(5-Bromo-pyridin-2-yl)-2-methyl-propionitrile

NaN[(SiCH₃)₃]₂ (1 M in tetrahydrofuran, 6.3 mL) was added dropwise to asolution of 2,5-dibromo-pyridine (1.50 g) and isobutyronitrile (0.58 mL)in toluene (15 mL) chilled in an ice bath and kept under argonatmosphere. The resulting mixture was further stirred with cooling for 1h and then at room temperature overnight. The mixture was filtered andthe filtrate was washed with water, 10% aqueous K₂CO₃ solution, andbrine. The organic phase was dried (MgSO₄) and the solvent wasevaporated. The residue was purified by chromatography on silica gel(dichloromethane/methanol 99:1->95:5) to furnish the title compound.Yield: 0.26 g (18% of theory); Mass spectrum (ESI⁺): m/z=220/222 (Br)[M+H]⁺.

EXAMPLE 195(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(5-methanesulfinyl-pyridin-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

The title compound was preparedfrom(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-oneand 2-bromo-5-methanesulfinyl-pyridine following a procedure analogousto that described in Example 171. Mass spectrum (ESI⁺): m/z=493 [M+H]⁺.

2-Bromo-5-methanesulfinyl-pyridine

The title compound was prepared from 2-bromo-5-methylsulfanyl-pyridinefollowing a procedure analogous to that described for5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI⁺):m/z=220/222 (Br) [M+H]⁺.

EXAMPLE 1962-[5-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridin-2-yl]-isobutyramide

Hydrogen peroxide (35% in water, 0.1 mL) was added to a mixture of2-[5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridin-2-yl]-2-methyl-propionitrile(0.21 g; for preparation see Example 194) and K₂CO₃ (0.03 g) inddimethyl sulfoxide (2 mL) at room temperature. After stirring themixture for 3 h at room temperature, another portion of hydrogenperoxide (35% in water, 0.1 mL) and K₂CO₃ (0.03 g) were added. Themixture was further stirred at room temperature for 1 h and at 40° C.overnight. After cooling to room temperature, little aqueous Na₂S₂O₃solution was added and then the mixture was concentrated. The residuewas purified by HPLC on reversed phase (methanol/water/ammonia) tofurnish the title compound. Yield: 0.03 g (14% of theory); Mass spectrum(ESI⁺): m/z=516 [M+H]⁺.

EXAMPLE 197 4108.1002-007 Example 225(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one

The title compound was prepared from(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-oneemploying a procedure analogous to that described in Example 1 Step 2,followed by a procedure analogous to that described in Example 71Step 1. LC-MS Method 2 t_(R)=1.463, min, m/z=435.2; ¹H NMR (CDCl₃) 1.51(d, 3H), 1.82-1.98 (m, 3H), 2.11-2.21 (m, 2H), 2.22-2.32 (m, 2H), 2.93(m, 1H), 3.53 (m, 2H), 5.66 (m, 1H), 6.93-7.01 (m, 4H), 7.22 (m, 1H),7.28 (m, 2H), 7.33 (m, 1H), 7.79 (m, 1H), 8.52 (m, 1H), 8.68 (m, 1H).

EXAMPLE 198(S)-3-((S)-1-(4-(6-(2-hydroxy-2-methylpropoxy)pyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of compound 1 (348 mg, 2.0 mmol) and K₂CO₃ (830 mg, 6.0mmol) in DMF (15 mL) was added ethyl 2-bromoacetate (668 mg, 4.0 mmol).The mixture was stirred at rt for 2 h, filtered, and the filtrate wasconcentrated in vacuo to give the crude final product, which waspurified by preparative TLC (1:1 PE/EtOAc) to afford ethyl2-(5-bromopyridin-2-yloxy)acetate (100 mg, 19.2%). ¹H NMR (CDCl₃): δ8.13 (s, 1H), 7.69-6.67 (d, 1H), 6.80-6.78 (d, 1H), 4.84 (s, 2H),4.25-4.20 (q, 2H), 1.28-1.25 (t, 3H) and ethyl2-(5-bromo-2-oxopyridin-1(2H)-yl)acetate (300 mg, 57.7%), ¹H NMR(CDCl₃): δ 7.41-7.26 (m, 2H), 6.53-6.5 (d, 1H), 4.59 (s, 2H), 4.28-4.21(q, 2H), 1.32-1.23 (q, 3H).

Step 2

To a solution of ethyl 2-(5-bromopyridin-2-yloxy)acetate (65 mg, 0.25mmol) in anhydrous THF (2 mL) was added MeMgBr (2.5 mL, 2.5 mmol)dropwise at −78° C. The reaction mixture was stirred at −78° C. for 1 h,quenched with satd aq NH₄Cl (5 mL), and extracted with EtOAc (3×10 mL).The combined organic layer was dried over anhydrous Na₂SO₄,concentrated, and purified by preparative TLC (1:1 PE/EtOAc) to afford1-(5-bromopyridin-2-yloxy)-2-methylpropan-2-ol (30 mg, 48.8%).

Step 3

To a solution of 1-(5-bromopyridin-2-yloxy)-2-methylpropan-2-ol (30 mg,0.122 mmol) in DME (6 mL) was added Pd(PPh₃)₄ (10 mg) under nitrogen.The mixture was stirred for 1 h at rt. A solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(58.4 mg, 0.122 mmol) in EtOH (2 mL) and satd aq NaHCO₃ (2 mL) wereadded. The mixture was stirred at 100° C. for 2 h, quenched with water,and extracted with EtOAc (3×10 mL). The combined organic layer was driedover anhydrous Na₂SO₄, concentrated, and purified by preparative TLC(1:1 PE/EtOAc) and HPLC to afford the title compound (7.6 mg, 12.1%). ¹HNMR (CDCl₃): δ 8.23 (d, 1H), 7.72 (q, 1H), 7.74-6.68 (m, 10H), 5.70 (m,1H), 4.24 (s, 2H), 3.43 (s, 1H), 2.85 (m, 1H), 2.40 (m, 1H), 2.27-2.14(m, 5H), 1.54 (d, 3H), 1.33-1.29 (d, 3H), 1.18-1.12 (d, 3H).

EXAMPLE 199N-cyclopropyl-5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxamide

Step 1

To a solution of methyl 4-methyl-3-oxopentanoate (72 g, 0.5 mol), andethylene glycol (56 g, 1 mol) in toluene (500 mL) was added4-methylbenzenesulfonic acid (1.9 g, 0.01 mol). The mixture was stirredat reflux with a Dean-Stark trap to remove water. The reaction mixturewas washed with a small amount of water and brine, dried over anhydrousNa₂SO₄, and concentrated in vacuum to give the crude methyl2-(2-isopropyl-1,3-dioxolan-2-yl)-acetate (67 g 71% yield), which wasused for the next step without further purification.

Step 2

In a flame-dried three neck flask equipped with an addition funnel,magnetic stirring bar, rubber septum, and a nitrogen inlet, was placedLiAlH₄ (3.12 g, 82.1 mmol) and THF (700 mL). After being cooled at 0°C., a solution of methyl 2-(2-isopropyl-1,3-dioxolan-2-yl)acetate (12 g,63.8 mmol) in THF (160 mL) was added dropwise with stirring. The mixturewas warmed to rt, and stirred for 24 hours. The reaction was quenched byadding water (5 mL), 15% aqueous NaOH (10 mL), and water (5 mL) slowly.The organic layer was separated, and the residue was extracted withEtOAc (3×100 mL). The combined organic phase was dried over Na₂SO₄, andconcentrated to afford the crude product, which was purified by columnchromatography to give 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (6.8 g,67%). ¹H NMR (CDCl₃): δ 0.90 (d, J=6.8 Hz, 6H), 1.87-1.96 (m, 3H), 2.81(br, 1H), 3.69-3.72 (m, 2H), 3.92-4.01 (m, 4H).

Step 3

To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (8.0 g, 50mmol) and triethylamine (23.5 mL, 170 mmol) in anhydrous CH₂Cl₂ (120 mL)was added methanesulfonyl chloride (11.6 mL, 150 mmol) at 0° C., and thereaction mixture was stirred at rt till the reaction was finished. Thereaction mixture was washed with water and brine, dried over Na₂SO₄,filtered, and concentrated to give the crude2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (12 g, crude),which was used for the next step without further purification.

Step 4

To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl methanesulfonate(12 g, 50 mmol) and (S)-1-(4-methoxyphenyl)-ethyl amine (19.9 g, 100mmol) in CH₃CN (250 mL) was added K₂CO₃ (8 g, 58 mmol), and the mixturewas refluxed for 10 h. The solution was filtered, and the filtrate wasconcentrated to afford the crude product, which was purified by columnchromatography to give(S)-1-(4-bromophenyl)-N-(2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl)ethanamine(6.5 g, 38% yield).

Step 5

To a solution of(5)-1-(4-bromophenyl)-N-(2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl)ethanamine(6.5 g, 19 mmol) in MeOH (60 mL) was added conc HCl (60 mL). The mixturewas stirred at 65° C. till the reaction was finished. The mixture wascooled to 0° C., and the pH of the mixture was adjusted to 7 by addingthe satd aq NaHCO₃. The mixture was concentrated, and the residue wasextracted with EtOAc (3×100 mL). The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to give(S)-1-(1-(4-bromophenyl)ethylamino)-4-methylpentan-3-one (5.5 g, 97%yield), which was used for the next step without further purification.¹H NMR (CDCl₃): δ 1.07 (d, J=6.8 Hz, 6H), 1.29 (d, J=6.4 Hz, 3H), 1.89(br, 1H), 2.54-2.62 (m, 4H), 2.66-2.69 (m, 1H), 3.68-3.72 (m, 1H),7.18-7.20 (m, 2H), 7.41-7.44 (m, 2H).

Step 6

To a suspension of Mg (11 g, 458 mmol) and I₂ (0.5 g) in anhydrous THF(50 mL) was added 3-chloro-2-methylprop-1-ene (1 mL) to initiate thereaction. THF (300 mL) was added, more solution of3-chloro-2-methylprop-1-ene (15 mL) in THF (20 mL) was dropped into thereaction at 0° C. under N₂ over 30 min. A solution of(S)-1-(1-(4-bromophenyl)-ethyl amino)-4-methylpentan-3-one (5 g) in THF(50 mL) was added dropwise at −78° C. over 45 min. The reaction wasstirred at rt for 2 h, cautiously quenched with satd aq NH₄Cl, andfiltered. The filtrate was extracted with EtOAc (3×100 mL), washed withbrine, dried over anhydrous Na₂SO₄, and concentrated in vacuo to give1-(S-1-(4-bromophenylamino)-3-isopropyl-5-methylhex-5-en-3-ol (6.4 g,90% yield), which was used for the next step without furtherpurification.

Step 7

To a solution of1-(S-1-(4-bromophenylamino)-3-isopropyl-5-methylhex-5-en-3-ol (6.4 g,16.8 mmol) and triethylamine (5.34 g, 52 mmol) in CH₂Cl₂ (260 mL) wasadded triphosgene (2.52 g, 8.5 mmol) at 0° C. under N₂, and the mixturewas stirred at rt overnight. The reaction mixture was quenched withwater, and extracted with CH₂Cl₂ (3×50 mL). The combined organic layerwas washed with brine, dried over Na₂SO₄, filtered, and concentrated toafford the crude product, which was purified by column chromatography togive two isomers of3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-methylallyl)-1,3-oxazinan-2-one.

Isomer 1: (1.85 g, 27% yield) ¹H NMR (CDCl₃): δ0.83 (d, J=7.2 Hz, 3H),0.89 (d, J=7.2 Hz, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.64-1.70 (m, 2H), 1.79(s, 3H), 1.88-1.95 (m, 1H), 2.20-2.34 (m, 2H), 2.59-2.65 (m, 1H),3.01-3.08 (m, 1H), 4.70 (s, 1H), 4.87 (s, 1H), 5.68-5.77 (m, 1H), 7.14(d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H).

Isomer 2: (1.25 g, 18% yield) ¹H NMR (CDCl₃): δ0.87 (d, J=6.8 Hz, 3H),0.92 (d, J=6.8 Hz, 3H), 1.50 (d, J=7.2 Hz, 3H), 1.60-1.66 (m, 1H), 1.78(s, 3H), 1.73-1.79 (m, 1H), 1.78-2.05 (m, 1H), 2.08 (d, J=14.0 Hz, 1H),2.30 (d, J=14.0 Hz, 1H), 2.62-2.68 (m, 1H), 2.98-3.05 (m, 1H), 4.64 (s,1H), 4.84 (s, 1H), 5.70-5.75 (m, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.40 (d,J=8.4 Hz, 2H).

Step 8

To a solution of3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-methylallyl)-1,3-oxazinan-2-one.isomer 1 (500 mg, 1.32 mmol) in dry CH₂Cl₂ (64 mL) was added m-CPBA (455g, 2.64 mmol) at rt. The reaction mixture was stirred until the startingmaterial was consumed (monitored by TLC). The mixture was diluted with(CH₃)₃COCH₃ (70 mL), washed with 30% Na₂S₂O₃, and aq NaHCO₃ (3×), driedover Na₂SO₄, filtered, and concentrated to give3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-((2-methyloxiran-2-yl)methyl)-1,3-oxazinan-2-oneisomer 1 (520 mg, 99%), which was used directly for the next stepwithout further purification.

Step 9

To a solution of3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-((2-methyloxiran-2-yl)methyl)-1,3-oxazinan-2-oneisomer 1 (520 mg, 1.32 mmol) in THF (32 mL) was added dropwise LiEt₃BH(Super-Hydride, 13.6 mL, 13.6 mmol) at 0° C. under N₂ over 30 min., theresulting solution was stirred at 10-13° C. for 21.5 h. To the mixturewas added H₂O₂ (40 mL). The resulting solution was diluted with(CH₃)₃COCH₃ (380 mL), and washed with water, 30% aq Na₂S₂O₃, and brine.The organic phase was dried over Na₂SO₄, and filtered. The filtrate wasconcentrated to give the crude product, which was purified by columnchromatography to afford3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazinan-2-oneisomer 1 (320 mg, 61%). ¹H NMR (CDCl₃): δ0.82 (d, J=6.8 Hz, 3H), 0.95(d, J=6.8 Hz, 3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.51 (d, J=10.0 Hz, 3H),1.61 (d, J=15.2 Hz, 1H), 1.78-1.84 (m, 1H), 1.91 (d, J=15.2 Hz, 1H),2.02-2.15 (m, 2H), 2.36 (br, 1H), 2.62-2.68 (m, 1H), 3.03-3.09 (m, 1H),5.73 (t, J=7.2 Hz, 1H), 7.17-7.19 (m, 2H), 7.44-7.48 (m, 2H).

Step 10

To a solution of3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-1,3-oxazinan-2-oneisomer 1 (315 mg, 0.793 mmol) in DMSO (10 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (602mg, 2.38 mmol), CH₃CO₂K (770 mg, 79.3 mmol), Pd(dppf)₂Cl₂ (50 mg, 0.06mmol) under N₂, the reaction was stirred at 90° C. for 4 h. The mixturewas quenched with NH₄Cl, and extracted with EtOAc, washed with water andbrine. The organic phase was dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to give the crude product, which was purifiedby preparative TLC to give6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneisomer 1 (250 mg, 71%).

Step 11

5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxylicacid was prepared from(S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-oneand 5-bromopyrimidine-2-carboxylic acid following a procedure analogousto that described in Example 1 Step 2.

Step 12

The title compound was prepared from5-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-6-isopropyl-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)pyrimidine-2-carboxylicacid and cyclopropylamine following a procedure analogous to thatdescribed in Example 25 Step 7.

EXAMPLE 200(S)-3-((S)-1-(4-(6-(2-fluoroethoxy)pyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one

Step 1

To a solution of 2-fluoroethanol (3.2 g, 50 mmol) and triethylamine (5.5g, 55 mmol) in dichloromethane (60 mL) was added dropwise (CF₃SO₂)₂O(15.5 g, 55 mmol) at −78° C. under N₂. The mixture was stirred at 10-20°C. for 1 h, and treated with water (100 mL). The organic layer waswashed with satd aq NaHCO₃ (100 mL) and brine (100 mL), dried, andconcentrated to give 2-fluoroethyl trifluoromethanesulfonate (8 g, yield82%).

Step 2

A solution of 5-bromopyridin-2(1H)-one (100 mg, 0.58 mmol),2-fluoroethyl trifluoromethanesulfonate (1.1 g, 5.8 mmol), and K₂CO₃(800 mg, 5.8 mmol) in DMF (3 mL) was stirred at rt overnight.2-Fluoroethyl trifluoromethanesulfonate (1.1 g, 5.8 mmol) and K₂CO₃ (800mg, 5.8 mmol) were added, and the mixture was treated with ethyl acetate(20 mL) and water (20 mL). The organic layer was washed with water (2×20mL) and brine (20 mL), dried over Na₂SO₄, concentrated, and purified bypreparative, TLC (1:1 petroleum ether/EtOAc) to give two isomers.

5-bromo-1-(2-fluoroethyl)pyridin-2(1H)-one (30 mg, yield 24%). ¹H NMR(CD₃OD): δ 4.25 (t, 1H), 4.32 (t, 1H), 4.62 (t, 1H), 4.74 (t, 1H), 6.52(d, 1H), 7.61 (dd, 1H), 7.85 (s, 1H).

5-bromo-2-(2-fluoroethoxy)pyridine (30 mg, yield 24%). ¹H NMR (CD₃OD):δ4.46 (t, 1H), 4.53 (t, 1H), 4.64 (t, 1H), 4.76 (t, 1H), 6.79 (d, 1H),7.79 (dd, 1H), 8.18 (s, 1H),

Step 3

To a solution of(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one(20 mg, 0.041 mmol), 5-bromo-2-(2-fluoroethoxy)pyridine (9.2 mg, 0.041mmol), and 2 N aq Cs₂CO₃ (0.2 mL, 0.41 mmol) in 1,4-dioxane (2 mL) wasadded Pd(PPh₃)₂Cl₂ (3 mg, 0.0041 mmol) under N₂. The mixture wasrefluxed for 2 h under N₂, treated with EtOAc (10 mL) and water (10 mL).The organic layer was dried over Na₂SO₄ and concentrated. The residuewas purified by preparative HPLC to give(S)-3-((S)-1-(4-(6-(2-fluoroethoxy)pyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one(2.20 mg, 11%). LC-MS Method 2 t_(R)=1.21 min, m/z=515, 493; ¹H NMR(CD₃OD): δ 0.95 (s, 3H), 1.26 (s, 3H), 1.54 (d, 3H), 2.15 (s, 2H), 2.21(m, 1H), 2.46 (m, 2H), 3.02 (m, 1H), 4.50 (t, 1H), 4.57 (t, 1H), 4.66(t, 1H), 4.79 (t, 1H), 5.57 (q, 1H), 6.88 (d, 1H), 7.02 (d, 2H), 7.31(m, 7H), 7.85 (dd, 1H), 8.25 (d, 1H).

EXAMPLE 201(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(1-isopropyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one

2 M aqueous Na₂CO₃ solution (0.75 mL) was added to a solution of4-bromo-1-isopropyl-1H-pyrazole (0.15 g) and(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.25 g) in dimethylformamide (2 mL). The resulting mixture was spargedwith argon for 10 min, before[1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II)dichloromethane complex (13 mg) was added. The mixture was heated to 90°C. and stirred at this temperature for 6 h. Then another portion of[1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro-palladium(II)dichloromethane complex (13 mg) was added and the mixture was furtherstirred at 100° C. overnight. After cooling to ambient temperature,water was added and the resulting mixture was extracted with ethylacetate. The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated. The residue was purified by HPLC on reversedphase (acetonitrile/water) followed by chromatography on silica gel(tert-butyl methyl ether/dichloromethane/NH₄OH 95:5:0.1) to afford thetitle compound as a solid. Yield: 23 mg (9% of theory); Mass spectrum(ESI⁺): m/z=462 [M+H]⁺.

EXAMPLE 2023-{(S)-1-[4-(1-Cyclopropyl-1H-pyrazol-4-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one

2 M aqueous Na₂CO₃ solution (0.37 mL) was added to a solution of4-bromo-1-isopropyl-1H-pyrazole (0.15 g) and(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.35 g) in dimethylformamide (3 mL). The resulting mixture was spargedwith argon for 10 min, before[1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II)dichloromethane complex (20 mg) was added. The mixture was heated to 90°C. and stirred at this temperature for 2 h. After cooling to ambienttemperature, water was added and the resulting mixture was extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried (MgSO₄), and concentrated. The residue was purified bychromatography on silica gel (tert-butyl methylether/dichloromethane/NH₄OH 96:4:0.1->94:6:0.1) to afford the titlecompound as a solid. Yield: 0.18 g (55% of theory); Mass spectrum(ESI⁺): m/z=460 [M+H]⁺.

4-Bromo-1-cyclopropyl-1H-pyrazole

A mixture of 4-bromo-1H-pyrazole (0.50 g), cyclopropylboronic acid (0.65g), copper(II) acetate (0.65 g), 2,2′-bipyridine (0.56 g), and sodiumcarbonate (0.80 g) in 1,2-dichloroethane (15 mL) was stirred at refluxtemperature for 4 h. Then another portion of cyclopropylboronic acid(0.65 g) and sodium carbonate (0.80 g) were added and the mixture wasfurther stirred at reflux temperature overnight. After cooling to roomtemperature, aqueous NH₄Cl solution was added and the resulting mixturewas extracted with dichloromethane. The combined extracts were dried(Na₂SO₄) and the solvent was evaporated. The residue was purified bychromatography on silica gel (cyclohexane/ethyl acetate 95:5->80:20) toafford the title compound as a colorless oil. Yield: 0.32 g (48% oftheory); Mass spectrum (ESI⁺): m/z=187/189 (Br) [M+H]⁺.

EXAMPLE 2036-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid dimethylamide

[(Benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammoniumtetrafluoroborate (TBTU, 110 mg) was added to a solution of6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid (140 mg) and ethyl-diisopropyl-amine (60 μL) inN,N-dimethylformamide (2 mL) at room temperature. The resulting solutionwas stirred for 20 min, before dimethylamine (2 mol/L intetrahydrofuran, 300 μL) was added. After stirring the solution at roomtemperature for another 2 h, the solution was concentrated and theresidue was purified by HPLC on reversed phase (methanol/water/NH₄OH) toafford the title compound. Yield: 50 mg (34% of theory); Mass spectrum(ESI⁺): m/z=503 [M+H]⁺.

6-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid

2 M aqueous Na₂CO₃ solution (1.46 mL) was added to a mixture of6-chloropyridazine-3-carboxylic acid methyl ester (0.38 g) and(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.70 g) in N,N-dimethylformamide (8 mL). The resulting mixture wassparged with argon for 10 min, before[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II)dichloromethane complex (72 mg) was added. The mixture was heated to100° C. and stirred at this temperature overnight. After cooling themixture to ambient temperature, water and 1 M hydrochloric acid wereadded and the resulting mixture was extracted with ethyl acetate. Thecombined organic extracts were washed with brine and dried (MgSO₄). Thesolvent was evaporated and the residue was purified by HPLC on reversedphase (methanol/water/F₃CCO₂H) to afford the title compound as an oilthat solidifies while standing. Yield: 0.36 g (52% of theory); Massspectrum (ESI⁻): m/z=474 [M−H]⁻.

EXAMPLE 2046-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid methylamide

The title compound was prepared from6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid and methylamine (2 mol/L in tetrahydrofuran) following a procedureanalogous to that described in Example 203. Mass spectrum (ESI⁺):m/z=489 [M+H]⁺.

EXAMPLE 2056-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid amide

The title compound was prepared from6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid and ammonia (32% in water) following a procedure analogous to thatdescribed in Example 203. Mass spectrum (ESI⁺): m/z=475 [M+H]⁺.

EXAMPLE 2066-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid dimethylamide

The title compound was prepared from(6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid and dimethylamine (2 mol/L in tetrahydrofuran) following aprocedure analogous to that described in Example 203. Mass spectrum(ESI⁺): m/z=502 [M+H]⁺.

6-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid ethyl ester

2 M aqueous Na₂CO₃ solution (1.46 mL) was added to a mixture of6-bromo-pyridine-2-carboxylic acid ethyl ester (0.50 g) and(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one(0.70 g) in N,N-dimethyl-formamide (8 mL). The resulting mixture wassparged with argon for 10 min, before[1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro-palladium(II)dichloromethane complex (72 mg) was added. The mixture was heated to100° C. and stirred at this temperature overnight. After cooling toambient temperature, water was added and the resulting mixture wasextracted with ethyl acetate. The combined organic extracts were dried(MgSO₄) and the solvent was evaporated. The residue was purified by HPLCon reversed phase (methanol/water/NH₄OH) to afford the title compound.Yield: 0.59 g (80% of theory); Mass spectrum (ESI⁺): m/z=503 [M+H]⁺.

6-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid

4 M aqueous NaOH solution (0.80 mL) was added to a solution of6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid ethyl ester (0.55 g) in methanol (3 mL) and the resulting solutionwas stirred at room temperature overnight. Then, the solution wasacidified using 1 M hydrochloric acid and the resulting mixture wasextracted with ethyl acetate. The combined organic extracts were washedwith brine and dried (MgSO₄). The solvent was evaporated to give thetitle compound. Yield: 0.49 g (95% of theory); Mass spectrum (ESI⁻):m/z=473 [M−H]⁻.

EXAMPLE 2076-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid methylamide

The title compound was prepared from(6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid and methylamine (2 mol/L in tetrahydrofuran) following a procedureanalogous to that described in Example 203. Mass spectrum (ESI⁺):m/z=488 [M+H]⁺.

EXAMPLE 2086-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid cyclopropylamide

The title compound was prepared from(6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid and cyclopropylamine following a procedure analogous to thatdescribed in Example 203. Mass spectrum (ESI⁺): m/z=514 [M+H]⁺.

EXAMPLE 2096-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid amide

The title compound was prepared from(6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylicacid and ammonia (32% in water) following a procedure analogous to thatdescribed in Example 203. Mass spectrum (ESI⁺): m/z=474 [M+H]⁺.

EXAMPLE 210(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one

The title compound was prepared from(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-oneand 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinefollowing a procedure analogous to that described in Example 14. LC-MSMethod 1 t_(R)=1.66 min, m/z=461.

BIOLOGICAL TEST EXAMPLE 1

The inhibition of a microsomal preparation of 11β-HSD1 by compounds ofthe invention was measured essentially as previously described (K.Solly, S. S. Mundt, H. J. Zokian, G. J. Ding, A. Hermanowski-Vosatka, B.Strulovici, and W. Zheng, High-Throughput Screening of11-Beta-Hydroxyseroid Dehydrogenase Type 1 in Scintillation ProximityAssay Format. Assay Drug Dev Technol 3 (2005) 377-384). All reactionswere carried out at rt in 96 well clear flexible PET Microbeta plates(PerkinElmer). The assay begins by dispensing 49 μl of substratesolution (50 mM HEPES, pH 7.4, 100 mM KCl, 5 mM NaCl, 2 mM MgCl₂, 2 mMNADPH and 160 nM [³H]cortisone (1 Ci/mmol)) and mixing in 1 μL of thetest compounds in DMSO previously diluted in half-log increments (8points) starting at 0.1 mM. After a 10 minute pre-incubation, 50 μL ofenzyme solution containing microsomes isolated from CHO cellsoverexpressing human 11β-HSD1 (10-20 μg/ml of total protein) was added,and the plates were incubated for 90 minutes at rt. The reaction wasstopped by adding 50 μl of the SPA beads suspension containing 10 μM18β-glycyrrhetinic acid, 5 mg/ml protein A coated YSi SPA beads (GEHealthcare) and 3.3 μg/ml of anti-cortisol antibody (East CoastBiologics) in Superbiock buffer (Bio-Rad). The plates were shaken for120 minutes at rt, and the SPA signal corresponding to [³H]cortisol wasmeasured on a Microbeta plate reader.

BIOLOGICAL TEST EXAMPLE 2

The inhibition of 11β-HSD1 by compounds of this invention was measuredin whole cells as follows. Cells for the assay were obtained from twosources: fully differentiated human omental adipocytes from Zen-Bio,Inc.; and human omental pre-adipocytes from Lonza Group Ltd.Pre-differentiated omental adipocytes from Zen-Bio Inc. were purchasedin 96-well plates and were used in the assay at least two weeks afterdifferentiation from precursor preadipocytes. Zen-Bio induceddifferentiation of pre-adipocytes by supplementing medium withadipogenic and lipogenic hormones (human insulin, dexamethasone,isobutylmethylxanthine and PPAR-gamma agonist). The cells weremaintained in full adipocyte medium (DMEM/Ham's F-12 (1:1, v/v), HEPESpH 7.4, fetal bovine serum, penicillin, streptomycin and Amphotericin B,supplied by Zen-Bio, Inc.) at 37° C., 5% CO₂.

Pre-adipocytes were purchased from Lonza Group Ltd. and placed inculture in Preadipocyte Growth Medium-2 supplemented with fetal bovineserum, penicillin, and streptomycin (supplied by Lonza) at 37° C., 5%CO₂. Pre-adipocytes were differentiated by the addition of insulin,dexamethasone, indomethacin and isobutyl-methylxanthine (supplied byLonza) to the Preadipocyte Growth Medium-2. Cells were exposed to thedifferentiating factors for 7 days, at which point the cells weredifferentiated and ready for the assay. One day before running theassay, the differentiated omental adipocytes were transferred intoserum- and phenol-red-free medium for overnight incubation. The assaywas performed in a total volume of 200 μL. The cells were pre-incubatedwith serum-free, phenol-red-free medium containing 0.1% (v/v) of DMSOand various concentrations of the test compounds at least 1 h before[³H] cortisone in ethanol (50 Ci/mmol, ARC, Inc.) was added to achieve afinal concentration of cortisone of 100 nM. The cells were incubated for3-4 hrs at 37° C., 5% CO₂. Negative controls were incubated withoutradioactive substrate and received the same amount of [³H] cortisone atthe end of the incubation. Formation of [³H] cortisol was monitored byanalyzing 25 μL of each supernatant in a scintillation proximity assay(SPA). (Solly, K.; Mundt, S. S.; Zokian, H. J.; Ding, G. J.;Hermanowski-Vosatka, A.; Strulovici, B.; Zheng, W. Assay Drug Dev.Technol. 2005, 3, 377-384). Many compounds of the invention showedsignificant activity in this assay.

TABLE OF BIOLOGICAL ASSAY RESULTS Biological Test EXAMPLE 4108.1002-007EXAMPLE 1 Average % inhibition at Compound IC₅₀ Range^(a) 100 nM EXAMPLE1 ++ 96.4 EXAMPLE 2 ++ 99.0 EXAMPLE 3 ++ 96.8 EXAMPLE 4 ++ 96.3 EXAMPLE5 Isomer 1 ++ 93.8 EXAMPLE 5 Isomer 2 ++ 88.8 EXAMPLE 6 ++ 96.3 EXAMPLE7 ++ 93.3 EXAMPLE 8 ++ 92.4 EXAMPLE 9 ++ 92.4 EXAMPLE 10 ++ 93.6 EXAMPLE11 ++ 91.6 EXAMPLE 12 ++ 47.0 EXAMPLE 13 ++ 92.1 EXAMPLE 14 ++ 93.4EXAMPLE 15 ++ 94.1 EXAMPLE 16 ++ 97.9 EXAMPLE 17 ++ 94.0 EXAMPLE 18 #13.7 EXAMPLE 19 ++ 94.6 EXAMPLE 20 ++ 92.2 EXAMPLE 21 ++ 99.2 EXAMPLE 22++ 90.0 EXAMPLE 23 ++ 89.3 EXAMPLE 24 ++ 96.9 EXAMPLE 25 Isomer 1 ++84.9 EXAMPLE 25 Isomer 2 ++ 90.5 EXAMPLE 26 ++ 95.2 EXAMPLE 27 ++ 96.8EXAMPLE 28 ++ 89.7 EXAMPLE 29 ++ 83.8 EXAMPLE 30 ++ 98.1 EXAMPLE 31 ++90.7 EXAMPLE 32 ++ 54.8^(b) EXAMPLE 33 + 37.1^(b) EXAMPLE 34 ++ 98EXAMPLE 35 ++ 96.3 EXAMPLE 36 ++ 93.3 EXAMPLE 37 ++ 94.3 EXAMPLE 38 ++87.3 EXAMPLE 39 ++ 73.6 EXAMPLE 40 ++ 93.4 EXAMPLE 41 ++ 96.8 EXAMPLE 42++ 90.9 EXAMPLE 43 ++ 86.2 EXAMPLE 44 ++ 100.1 EXAMPLE 45 ++ 96.7EXAMPLE 46 ++ 93.4 EXAMPLE 47 ++ 91 EXAMPLE 48 ++ 94.3 EXAMPLE 49 ++96.7 EXAMPLE 50 ++ 81.2 EXAMPLE 51 ++ 96.1 EXAMPLE 52 ++ 94.5 EXAMPLE 53++ 98.7 EXAMPLE 54 ++ 97.1 EXAMPLE 55 ++ 96.5 EXAMPLE 56 ++ 96.7 EXAMPLE57 ++ 99.4 EXAMPLE 58 ++ 97.4 EXAMPLE 59 ++ 100.5 EXAMPLE 60 ++ 91.9EXAMPLE 61 ++ 96.2 EXAMPLE 62 ++ 97.9 EXAMPLE 63 ++ 101.1 EXAMPLE 64 ++99.6 EXAMPLE 65 ++ 99 EXAMPLE 66 ++ 95.6 EXAMPLE 67 ++ 100.9 EXAMPLE 68++ 50 EXAMPLE 69 ++ 98.3 EXAMPLE 70 ++ 49.7 EXAMPLE 71 ++ 68.7 EXAMPLE72 ++ 64.8 EXAMPLE 73 ++ 65.3 EXAMPLE 74 ++ 95.7 EXAMPLE 75 ++ 97.7EXAMPLE 76 ++ 98.7 EXAMPLE 77 ++ 79.9 EXAMPLE 78 ++ 95.8 EXAMPLE 79 ++76.9 EXAMPLE 80 ++ 96 EXAMPLE 81 ++ 99.3 EXAMPLE 82 ++ 98.1 EXAMPLE 83++ 94.7 EXAMPLE 84 ++ 93.3 EXAMPLE 85 ++ 94.3 EXAMPLE 86 ++ 99.6 EXAMPLE87 ++ 99.8 EXAMPLE 88 ++ 98.3 EXAMPLE 89 ++ 98.9 EXAMPLE 90 ++ 96.7EXAMPLE 91 ++ 90.2 EXAMPLE 92 ++ 97.3 EXAMPLE 93 ++ 101.5 EXAMPLE 94 ++98.7 EXAMPLE 95 ++ 93.9 EXAMPLE 96 ++ 99.8 EXAMPLE 97 ++ 98.8 EXAMPLE 98++ 97.8 EXAMPLE 99 ++ 98.5 EXAMPLE 100 ++ 93.1 EXAMPLE 101 ++ 100.4EXAMPLE 102 ++ 94.3 EXAMPLE 103 ++ 98.5 EXAMPLE 104 ++ 88 EXAMPLE 105 ++86.3 EXAMPLE 106 ++ 79.6 EXAMPLE 107.1 ++ 95.5 EXAMPLE 107.2 ++ 93.6EXAMPLE 108 ++ 98.1 EXAMPLE 109 ++ 91.5 EXAMPLE 110 ++ 93.9 EXAMPLE 111++ 97.6 EXAMPLE 112 ++ 95.2 EXAMPLE 113 ++ 92.4 EXAMPLE 114 ++ 98.9EXAMPLE 115 ++ 95.1 EXAMPLE 116 ++ 99.6 EXAMPLE 117 ++ 93.9 EXAMPLE 118++ 86.3 EXAMPLE 119 ++ 90.8 EXAMPLE 120 ++ 93.1 EXAMPLE 121 ++ 97.3EXAMPLE 122 ++ 94.5 EXAMPLE 123 ++ 93.6 EXAMPLE 124 ++ 88.1 EXAMPLE 125++ 98.6 EXAMPLE 126 ++ 96.7 EXAMPLE 127 ++ 93.7 EXAMPLE 128 ++ 96.5EXAMPLE 129 ++ 93.9 EXAMPLE 130 ++ 97.9 EXAMPLE 131 ++ 98.5 EXAMPLE 132++ 95.2 EXAMPLE 133 ++ 99.2 EXAMPLE 134 ++ 97.6 EXAMPLE 135 ++ 97.3EXAMPLE 136 ++ 97.8 EXAMPLE 137 ++ 99 EXAMPLE 138 ++ 100 EXAMPLE 139 ++97.6 EXAMPLE 140 ++ 98.7 EXAMPLE 141 ++ 101.9 EXAMPLE 142 ++ 96.4EXAMPLE 143 ++ 97.6 EXAMPLE 144 ++ 98.6 EXAMPLE 145 ++ 72.4 EXAMPLE 146++ 78.9 EXAMPLE 147 ++ 98.7 EXAMPLE 148 ++ 97.4 EXAMPLE 149 ++ 95.5EXAMPLE 150 ++ 97 EXAMPLE 151 ++ 97 EXAMPLE 152 ++ 65.4 EXAMPLE 153 ++94.7 EXAMPLE 154 ++ 90.7 EXAMPLE 155 ++ 94.7 EXAMPLE 156 ++ 96.4 EXAMPLE157 ++ 96.3 EXAMPLE 158 ++ 95.7 EXAMPLE 159 ++ 94.6 EXAMPLE 160 ++ 95EXAMPLE 161 ++ 95.1 EXAMPLE 162 ++ 87.2 EXAMPLE 163 ++ 90.3 EXAMPLE 164++ 99.4 EXAMPLE 165 ++ 94.5 EXAMPLE 166 ++ 96.5 EXAMPLE 172 ++ 97.9EXAMPLE 183 ++ 96.4 EXAMPLE 186 ++ 95.2 EXAMPLE 197 ++ 96.5 EXAMPLE 198++ 92.4 EXAMPLE 199 ++ 62.9 EXAMPLE 200 ++ 98.3 EXAMPLE 210 ++ 97.1^(a)++ means IC₅₀ = <100 nM, + means IC₅₀ = 100-1000 nM, # means IC₅₀ >100 nM, − means IC₅₀ > 1000 nM; ^(b)average % inhibition at 111 nM.

BIOLOGICAL TEST EXAMPLE 3

In vitro inhibition of 11 β-HSD1 by test compounds was determined withHTRF (Homogeneous Time-Resolved Fluorescence) technology (cisbiointernational, France) detecting cortisol generated from cortisterone byhuman liver microsomes. Briefly, compounds were incubated for 1 hour at37° C. in Tris buffer (20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH(200 μM) and cortisone (80 nM). Cortisol generated in the reaction isthen detected with a competitive immunoassay, involving two HTRFconjugates: cortisol linked to XL665 and anti-cortisol antibody labeledwith Europium cryptate. The incubation period for detection reaction wastypically 2 hours. The amount of cortisol was determined by reading thetime-resolved fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and665/7.5 nm). The ratio of the two emission signals was then calculated(Em665*10000/Em615). Each assay contained incubations with vehiclecontrols instead of compound as controls for non-inhibited cortisolgeneration (100% CTL; ‘high values’) and incubations with carbenoxoloneas controls for fully inhibited enzyme and cortisol background (0% CTL;‘low values’). Each assay also contained a calibration curve withcortisol to transform the fluorescent data into cortisol concentrations.Percent inhibition of each compound was determined relative to thecarbenoxolone signal.

In the following table are compiled the 11β-HSD 1 inhibitory activitiesof the compounds Example 167 to Example 196, Example 201, and Example203-209 determined as described above, wherein 100% indicates noinhibition and a value of zero or below zero indicates completeinhibition.

TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TEST 3 Average %control Example inhibition at 100 nM 167 43 168 −32 169 −19 170 −8 171−14 172 1 173 31 174 6 175 −4 176 15 177 23 178 −19 179 27 180 11 181 60182 2 183 −5 184 51 185 30 186 3 187 9 188 45 189 42 190 −15 191 −2 19222 193 11 194 17 195 −2 196 18 201 −1 203 37 204 23 205 12 206 18 207 −8208 24 209 18

BIOLOGICAL TEST EXAMPLE 4

The inhibition of a microsomal preparation of 11β-HSD1 in the presenceof 50% human plasma by compounds of the invention was measured asfollows. Microsomes from CHO cells overexpressing human 11β-HSD1 werediluted into reaction buffer consisting of 25 mM HEPES, pH 7.4, 50 mMKCl, 2.5 mM NaCl, 1 mM MgCl2, and 50% (v/v) human plasma (BioChemed).The assay began by dispensing 49 μl of microsome solution into 96-wellpolypropylene plates and adding 1 μl of the test compounds in DMSO,previously diluted in half-log increments (8 points) starting at 1.0 mM.The reaction was initiated with the addition of 50 μl substrate solutionconsisting of reaction buffer with 2 mM NADPH and 160 nM [³-H]cortisone(1 Ci/mmol). The plates were incubated for 120 minutes at rt, and thereaction was quenched with the addition of 100 μl acetonitrile with 20mM cortisone and 20 mM cortisol. After a ten minute incubation at rt,100 μl of each well was filtered through a MultiScreen HTS, HV filterplate (Millipore) and diluted with 100 μl of reaction buffer withouthuman plasma. [³-H]cortisone and [³-H]cortisol were separated by HPLC ona Zorbax SB-C8 column (4.6×250 mm, Agilent) with an isocratic elution at25% acetonitrile in water with 0.01% trifluoroacetic acid, andradioactivity was quantified with an in-line β-RAM (IN/US Systems,Inc.).

BIOLOGICAL TEST EXAMPLE 5 Fraction Unbound in Human Plasma

Plasma protein binding of compounds was determined with EquilibriumDialysis of spiked plasma against compound free dextrane buffer using adialysis membrane with mass cutoff of 5000 Da. Compound concentrationsin plasma and buffer after incubation were measured using HPLC/Massspectrometry.

BIOLOGICAL TEST EXAMPLE 6 CYP3A4 Inhibition

The assay is based on a method published by Moody et al. (Xenobiotica1999). The inhibition of cytochrome P450 3A4-isoenzyme catalysedN-demethylation of [N-methyl-14C]-Erythromycin by the test compound wasassayed at 37° C. with human recombinant cytochrome P450 3A4. All assayswere carried out on a robotic system in 96 well plates. The finalincubation volume of 200 μl contains TRIS buffer (0.1 M), MgCl₂ (5 mM),recombinant protein (40 pmol/ml), Erythromycin (50 μM) and the testcompound either at four different concentrations in duplicate (e.g.highest concentration 10-50 μM with subsequent serial 1:5 dilutions) orat a concentration of 10 μM in triplicate. Following a shortpreincubation period, reactions were started with the cofactor (NADPH, 1mM) and stopped by addition of 50 μl aqueous trichloroacetic acid (10%;w/v). An aliquot of the incubate was transferred to 96 well solid phaseextraction (SPE) plates and extracted on the cartridge. The resultant[¹⁴C]-formaldehyde/formic acid was not retained on the cartridge and wastherefore separated from the unmetabolized substrate by washing the SPEplates with water. An aliquot of the eluates was transferred into wellplates suitable for liquid scintillation counting. The rate of formationof [¹⁴C]-formaldehyde/formic acid in these incubations was compared to acontrol activity containing no test compound. If the compound was testedat four concentrations, experimental IC₅₀ values were calculated.

BIOLOGICAL TEST EXAMPLE 7 CYP2C9 Inhibition

Using a procedure similar to that described in Biological Test Example6, the inhibition of cytochrome P450 2C9-isoenzyme catalysedO-demethylation of [O-methyl-¹⁴C]-Naproxen by the test compound wasassayed at 37° C. with human recombinant cytochrome P450 2C9. Theexperimental IC₅₀ was calculated based on % control at four differentconcentrations.

BIOLOGICAL TEST EXAMPLE 8 CYP2C19 Inhibition

Using a procedure similar to that described in Biological Test Example6, the inhibition of cytochrome P450 2C19-isoenzyme catalysedN-demethylation of [N-methyl-¹⁴C]-Diazepam by the test compound wasassayed at 37° C. with human recombinant cytochrome P450 2C19. Theexperimental IC₅₀ was calculated based on % control at four differentconcentrations.

BIOLOGICAL TEST EXAMPLE 9 CYP2C9 Inhibition

The inhibition of recombinant CYP2C9 by compounds of the invention wasmeasured using a commercial kit from Invitrogen (cat #2859). Suppliedmicrosomes isolated from insect cells infected with a baculovirusengineered to express human CYP2C9 were diluted to 10 mM in reactionbuffer (100 mM potassium phosphate buffer, pH 8.0) with an NADPHgeneration system (3.33 mM glucose-6-phosphate and 0.4 U/mlglucose-6-phosphate dehydrogenase). 89 μl of this dilution weredispensed to each well of a 96-well, black, polystyrene plate and mixedwith 1 μl of test compound previously diluted in DMSO in half logincrements starting at 3 mM. The assay was initiated by adding 10 μl offluorogenic substrate n-octyloxymethylresorufin (OOMR, 20 μM.) with NADP(100 μM) diluted in reaction buffer. The plate was immediately placed ina Perkin Elmer Fusion plate reader. Reaction progress was monitored bymeasuring fluorescence every two minutes for a total of twenty minutes(530 nM excitation filter/605 nM emission filter).

TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TESTS 1 AND 4Biological Biological Biological Test Test Test Example 1 Example 4^(a)Example 5 EXAMPLE IC₅₀ (nM) IC₅₀ (nM) Shift^(b) (%) 1 0.7 7.3 10.4 2 0.82.9 3.8 3 1.0 7.9 8.0 4 0.7 4.0 5.8 5 Isomer 1 1.4 24.8 17.2 5 Isomer 28.7 17.0 1.9 6 1.0 8.6 8.4 7 4.9 4.3 0.9 8 2.8 11.2 4.0 9 1.3 5.1 3.9 102.5 7.5 3.1 11 1.0 3.4 3.5 12 96.6 nt 13 1.8 10.5 5.8 14 0.9 4.5 5.0 151.7 4.2 2.4 16 0.8 5.5 6.9 17 2.2 5.7 2.5 18 >100.0 nt 19 1.9 19.8 10.420 1.7 8.1 4.7 21 0.4 3.4 7.8 22 2.8 18.1 6.6 23 2.7 13.7 5.1 24 0.8 4.45.2 25 Isomer 1 14.8 nt 25 Isomer 2 6.5 nt 26 1.7 6.8 4.1 27 1.2 4.7 3.828 1.4 185.5 129.7 29 12.2 nt 30 0.9 21.8 24.0 31 4.8 9.3 1.9 32 54.0 nt33 305.2 nt 34 1.0 15.9 16.1 35 1.0 2.8 2.9 36 1.0 19.5 18.6 37 2.5 6.12.5 38 3.7 8.1 2.2 39 5.2 nt 40 2.3 28.6 12.4 41 1.9 11.0 5.8 42 1.034.3 33.4 43 8.6 315.5 36.5 44 0.7 4.2 5.7 45 3.0 13.5 4.6 46 0.8 nt 472.6 21.4 8.3 48 1.0 3.9 3.8 49 0.5 7.8 15.8 50 29.1 nt 51 1.5 60.7 40.652 1.1 10.5 9.3 1.8 53 1.3 18.5 14.6 54 1.0 39.4 38.4 55 1.5 8.3 5.6 560.7 5.5 8.0 57 1.0 19.2 18.8 58 0.8 7.2 9.0 59 0.5 5.1 9.9 60 1.6 20.813.1 61 0.7 13.6 18.2 62 0.5 22.6 44.2 63 0.8 15.2 18.4 64 0.8 6.2 8.265 0.4 3.8 8.8 66 1.3 9.7 7.4 67 0.7 6.7 9.9 68 85.1 nt 69 0.6 6.3 9.870 99.6 nt 71 44.1 nt 72 43.5 nt 73 46.9 nt 74 1.4 4.7 3.5 75 1.1 9.88.6 76 0.8 6.9 8.8 77 38.1 114.1 3.0 78 1.8 19.8 11.2 79 28.3 nt 80 1.05.5 5.4 81 0.6 nt 82 1.8 25.2 14.1 83 1.0 8.8 8.9 84 3.5 12.4 3.5 85 0.912.9 13.6 86 0.6 6.4 11.1 87 0.7 8.1 12.0 88 1.7 9.9 6.0 89 0.6 6.2 10.590 0.5 13.5 25.5 91 1.4 13.7 9.9 92 0.5 12.7 23.7 93 0.6 10.2 18.2 940.5 5.0 11.0 95 1.2 120.5 99.6 96 0.7 5.6 7.9 97 1.0 10.8 11.1 98 1.46.3 4.5 99 0.5 7.9 16.6 100 1.2 6.0 4.8 101 1.2 7.5 6.0 102 3.6 63.017.3 103 1.9 8.2 4.3 104 9.2 nt 105 19.2 nt 106 22.7 nt 107 Isomer 1 3.286.4 26.9 107 Isomer 2 3.2 269.4 83.8 108 1.8 7.1 4.0 109 2.9 31.9 11.0110 0.5 3.7 7.7 111 0.8 7.2 8.9 2 112 0.5 8.1 15.2 113 7.4 22.8 3.1 1140.9 3.9 4.5 115 1.0 10.3 10.2 116 0.7 3.7 5.1 117 1.7 12.1 7.3 118 19.2nt 119 2.0 29.7 15.1 120 6.7 24.2 3.6 121 2.3 7.5 3.3 122 2.5 6.5 2.6123 6.6 11.1 1.7 124 5.6 14.5 2.6 125 0.6 6.8 12.3 126 1.5 13.3 8.7 1276.1 69.8 11.5 128 1.1 8.5 7.8 129 4.3 17.3 4.1 130 2.5 21.6 8.8 1.9 1312.2 5.1 2.3 132 6.1 18.9 3.1 133 1.3 10.2 7.8 134 1.3 5.6 4.3 10.5 1351.8 5.4 3.1 136 0.8 5.7 7.3 0.3 137 2.2 10.7 4.8 138 1.1 7.5 7.0 2 1392.6 16.1 6.2 140 1.1 6.8 6.4 141 1.0 6.6 6.3 142 2.6 8.1 3.1 143 1.6 5.53.4 144 1.2 12.0 9.8 145 32.8 nt 146 17.4 nt 147 0.9 7.9 9.3 148 0.7 4.87.3 149 2.5 32.4 12.9 2.7 150 1.5 7.4 5.1 151 1.0 9.2 9.4 152 39.6 nt153 1.7 9.2 5.4 154 3.5 13.2 3.8 155 2.1 6.4 3.0 156 1.1 10.1 9.2 1572.9 27.4 9.6 158 2.1 12.9 6.2 159 3.3 7.3 2.2 160 1.0 17.4 17.5 161 1.13.9 3.7 162 1.4 31.7 21.9 163 1.6 5.9 3.8 164 1.2 22.2 18.2 165 2.4 42.517.4 166 1.0 2.3 2.3 167 nt nt 168 nt nt 172 3.3 10.6 3.2 183 0.93 1860.90 197 1.1 5.7 5.0 198 1.0 199 63.5 nt 200 0.96 18.3 19.1 210 0.6^(a)nt means not tested; ^(b)Shift is the IC₅₀ determined in BiologicalTest Example 4 divided by the IC₅₀ determined in Biological Test Example1.

TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TESTS 6-9 BiologicalBiological Biological Biological Test Test Test Test Example 6 Example 7Example 8 Example 9 CYP3A4, CYP2C9, CYP2C19, CYP2C9 EXAMPLE IC₅₀ [μM]IC₅₀[ μM] IC₅₀ [μM] IC₅₀ [μM] 1 16.7 12.9 10.1 2 3 2.1 2.5 3.0 4 19.619.8 24.2 5 Isomer 1 5 Isomer 2 0.6 6 7 5.3 8 9 48.9 >50.0 0.8 10 34.921.2 14.5 11 8.7 >50.0 3.7 12 4.0 13 >10.0 >10.0 >10.0 14 20.115 >50.0 >50.0 12.5 16 24.9 >50.0 6.1 17 45.3 17.8 5.9 18 19 27.1 31.710.3 20 49.8 15.4 47.7 21 22 5.2 4.5 3.6 23 24 25 Isomer 1 25 Isomer 226 27 28 29 30 31 32 33 34 5.1 35 2.2 36 5.2 37 8.5 38 >30.0 39 40 10.041 20.5 42 43 44 1.4 45 9.0 46 47 27.4 48 5.4 49 8.4 50 51 0.7 52 >50.017.9 37.9 9.6 53 6.6 54 0.4 55 14.1 56 6.1 57 58 16.9 59 10.9 60 61 29.223.0 40.0 9.9 62 10.9 63 64 4.7 65 4.0 66 5.3 67 3.8 68 69 2.3 70 71 7273 74 2.9 75 14.9 12.2 12.2 9.1 76 5.0 2.9 8.5 7.9 77 78 7.3 4.8 5.3 8.779 80 13.0 11.2 13.2 8.9 81 82 83 3.9 84 85 86 87 88 23.7 89 13.3 90 9117.3 92 93 11.6 8.0 11.4 8.0 94 4.5 95 2.4 96 97 8.9 11.2 19.5 9.7 9842.2 36.7 31.3 >30.0 99 100 4.5 101 >50.0 9.9 >50.0 102 103 104 105 2.5106 9.5 107 Isomer 1 2.7 107 Isomer 2 17.5 108 109 110 1119.8 >50.0 >50.0 4.7 112 6.1 113 2.9 114 115 4.4 116 5.3 117 118 119 1204.7 121 4.8 122 123 9.1 124 125 4.3 126 127 >30.0 128 3.3 129 28.3 13011.8 >50.0 3.0 9.7 131 5.6 14.0 2.6 11.2 132 18.3 133 >30.0134 >50.0 >50.0 >50.0 >30.0 135 22.8 44.4 35.8 136 24.1 20.1 24.7 9.6137 18.4 138 12.7 22.2 24.2 139 >50.0 21.4 18.2 9.9 140 20.6 141 >30.0142 143 >50.0 >50.0 >50.0 144 11.9 10.2 9.6 145 >30.0 146 6.1 147 4.6148 1.7 149 >50.0 >50.0 >50.0 17.4 150 50.0 28.8 33.8 151 50.0 32.6 32.3152 153 154 155 >50.0 38.9 >50.0 156 >50.0 >50.0 47.6 157158 >50.0 >50.0 >50.0 159 160 4.5 2.3 1.7 161 >50.0 36.0 10.5 162 16315.9 6.9 10.9 164 165 166 20.7 9.0 39.5 167 46.7 29.5 26.1 168 16.8 15.17.9 169 28.4 45.2 5.9 170 45.6 48.6 39.4 171 <0.4 9.2 0.8 172 >50.0 38.144.4 173 25.1 27.2 33.6 174 5.4 7.8 1.0 175 9.7 29.8 1.8 176 7.5 6.0 7.9177 >50.0 8.8 17.7 178 >50.0 21.3 >50.0 179 21.1 10.7 17.0 180 9.8 9.214.4 181 7.8 5.6 8.2 197 14.3 182 >50.0 >50.0 >50.0 183 >50.0 45.7 47.4184 >50.0 >50.0 >50.0 185 42.9 30.0 25.7 186 >50.0 >50.0 48.6 187 >50.025.9 >50.0 188 42.4 21.2 >50.0 189 >50.0 >50.0 >50.0 19033.7 >50.0 >50.0 191 36.4 >50.0 >50.0 192 11.2 10.4 15.5 193 26.6 24.233.3 194 195 196 198 199 200 201

TABLE OF BIOLOGICAL ASSAY RESULTS FOR COMPARATOR COMPOUNDS IN BIOLOGICALTESTS 1, 4 AND 5 Biological Biological Biological Comparator TestExample 1 Test Example 4^(a) Test Example 5 Compound IC₅₀ (nM) IC₅₀ (nM)Shift^(b) (%) 1 0.77 11.97 15.51 2 1.80 14.16 7.88 3 0.75 17.74 23.630.3 4 1.44 15.24 10.57 5 0.51 18.50 36.10 6 1.48 37.58 25.39 7 0.9941.90 42.43 8 0.72 17.85 24.74 9 0.55 11.86 21.45 0.3 10 1.79 53.4929.91 11 0.55 13.40 24.59 0.7 12 1.08 19.54 18.12 0.4 13 0.76 6.32 8.3014 1.30 8.94 6.90 15 0.79 8.94 11.32 ^(a)nt means not tested; ^(b)Shiftis the IC₅₀ determined in Biological Test Example 4 divided by the IC₅₀determined in Biological Test Example 1.

TABLE OF BIOLOGICAL ASSAY RESULTS FOR COMPARATOR COMPOUNDS IN BIOLOGICALTESTS 6-9 Biological Biological Biological Biological Test Test TestTest Example 6 Example 7 Example 8 Example 9 Comparator CYP3A4, CYP2C9,CYP2C19, CYP2C9 Compound IC₅₀ [μM] IC₅₀ [μM] IC₅₀ [μM] IC₅₀ [μM] 1 27.02 1.4 3 7.4 4.1 5.7 4.9 4 5.1 5 9.9 5.1 8.3 3.7 6 4.4 2.3 8.6 5.0 7 4.08 5.3 2.4 5.6 3.0 9 7.0 3.1 9.3 2.5 10 3.6 11 14.1 6.3 12.5 5.5 12 4.94.6 9.5 2.5 12 4.9 3.9 10.1 13 4.4 5.6 <0.4 7.3 14 19.7 25.9 6.4 24.6 153.1 7.7 <0.4 9.5

Comparator 1

Comparator 2

Comparator 3

Comparator 4

Comparator 5

Comparator 6

Comparator 7

Comparator 8

Comparator 9

Comparator 10

Comparator 11

Comparator 12

Comparator 13

Comparator 14

Comparator 15

The compounds of the invention are useful for ameliorating or treatingdisorders or diseases in which decreasing the level of cortisol iseffective in treating a disease state. Thus, the compounds of theinvention can be used in the treatment or prevention of diabetesmellitus (e.g., type II diabetes), obesity, symptoms of metabolicsyndrome, glucose intolerance, hyperglycemica, hypertension,hyperlipidemia, insulin resistance, cardiovascular disease,dyslipidemia, atherosclerosis, lipodystrophy, osteoporosis, glaucoma,Cushing's syndrome, Addison's Disease, visceral fat obesity associatedwith glucocorticoid therapy, depression, anxiety, Alzheimer's disease,dementia, cognitive decline (including age-related cognitive decline),polycystic ovarian syndrome, infertility and hypergonadism. Thecompounds of the invention can be used as therapeutic agents for pseudoCushing's Syndrome associated with alcoholic liver disease. In addition,the compounds modulate the function of B and T cells of the immunesystem and can therefore be used to treat diseases such as tuberculosis,leprosy and psoriasis. They can also be used to promote wound healing,particularly in diabetic patients.

Additional diseases or disorders that are related to 11β-HSD1 activityinclude those selected from the group consisting of lipid disorders,hypretriglyceridemia, hypercholesterolemia, low HDL levels, high LDLlevels, vascular restenosis, pancreatitis, abdominal obesity,neurodegenerative disease, retinopathy, nephropathy, neuropathy,diabetes, coronary heart disease, stroke, peripheral vascular disease,Cushing's syndrome, hyperinsulinemia, viral diseases, and Syndrome X. Afurther disease related to 11β-HSD1 activity is pseudo Cushing'sSyndrome associated with alcoholic liver disease.

A pharmaceutical composition of the invention may, alternatively or inaddition to an 11β-HSD1 inhibitor of the invention, comprise apharmaceutically acceptable salt of a an 11β-HSD1 inhibitor of theinvention and one or more pharmaceutically acceptable carrierstherefore. Alternatively, a pharmaceutical composition of the inventionmay comprise a compound of an 11β-HSD1 inhibitor of the invention or apharmaceutical salt thereof as the only pharmaceutically active agent inthe pharmaceutical composition. The disclosed 11β-HSD1 inhibitors can beused alone or in a combination therapy with one or more additionalagents for the treatment of diabetes, dyslipidemia, cardiovasculardisease, hypertension, obesity, cancer or glaucoma.

The compositions of the invention are 11β-HSD1 inhibitors. Saidcompositions contain compounds having a mean inhibition constant (IC₅₀)against 11β-HSD1 of below about 1,000 nM; preferably below about 100 nM;more preferably below about 50 nM; even more preferably below about 5nM; and most preferably below about 1 nM.

The invention includes a therapeutic method for treating or amelioratingan 11β-HSD1 mediated disorder in a subject in need thereof comprisingadministering to a subject in need thereof an effective amount of an11β-HSD1 inhibitor of the invention, or an enantiomer, diastereomer, orpharmaceutically acceptable salt thereof or composition thereof. As usedherein, “treating” or “treatment” includes both therapeutic andprophylactic treatment. Therapeutic treatment includes reducing thesymptoms associated with a disease or condition and/or increasing thelongevity of a subject with the disease or condition. Prophylactictreatment includes delaying the onset of a disease or condition in asubject at risk of developing the disease or condition or reducing thelikelihood that a subject will then develop the disease or condition ina subject that is at risk for developing the disease or condition.

An embodiment of the invention includes administering an 11β-HSD1inhibiting compound of the invention or composition thereof in acombination therapy with one or more additional agents for the treatmentof diabetes, dyslipidemia, cardiovascular disease, hypertension,obesity, cancer or glaucoma. Agents for the treatment of diabetesinclude insulins, such as Humulin® (Eli Lilly), Lantus® (SanofiAventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPAR gammaagonists, such as Avandia® (rosiglitizone maleate, GSK) and Actos®(pioglitazone hydrochloride, Takeda/Eli Lilly); sulfonylureas, such asAmaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, SanofiAventis), Micronase®/Glynase® (glyburide, Pfizer), andGlucotrol®/Glucotrol XL® and (glipizide, Pfizer); meglitinides, such asPrandin®/NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide,Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such asGlucophase®/Glucophase XR® (metformin HCl, Bristol Myers Squibb) andGlumetza (metformin HCl, Depomed); thiazolidinediones; amylin analogs,GLP-1 analogs; DPP-IV inhibitors; PTB-1B inhibitors; protein kinaseinhibitors (including AMP-activated protein kinase inhibitors); glucagonantagonists, glycogen synthase kinase-3 beta inhibitors;glucose-6-phoshatase inhibitors; glycogen phosphorylase inhibitors;sodium glucose co-transporter inhibitors, and alpha-glucosidaseinhibitors, such as Precose®/Glucobay®/Prandase®/Glucor® (acarbose,Bayer) and Glyset® (miglitol, Pfizer). Agents for the treatment ofdyslipidemia and cardiovascular disease include statins, fibrates, andezetimbe. Agents for the treatment of hypertension includealpha-blockers, beta-blockers, calcium channel blockers, diuretics,angiotensin converting enzyme (ACE) inhibitors, dual ACE and neutralendopeptidase (NEP) inhibitors, angiotensin-receptor blockers (ARBs),aldosterone synthase inhibitors, aldosterone-receptor antagonists, orendothelin receptor antagonist. Agents for the treatment of obesityinclude orlistat, phentermine, sibutramine and rimonabant.

An embodiment of the invention includes administering an 11β-HSD1inhibiting compound of the invention or composition thereof in acombination therapy with one or more other 11β-HSD1 inhibitors, or withcombination products, such as Avandamet® (metformin HCl androsiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazonemaleate, GSK); Metaglip® (glipizide and metformin HCl, Bristol MyersSquibb); and Glucovance® (glyburide and metformin HCl, Bristol MyersSquibb).

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Additionally, thecompounds of the present invention can be administered intranasally ortransdermally. It will be obvious to those skilled in the art that thefollowing dosage forms may comprise as the active ingredient, eithercompounds or a corresponding pharmaceutically acceptable salt of acompound of the present invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can either besolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier is a finely dividedsolid which is in a mixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from about one to aboutseventy percent of the active ingredient. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcaboxymethylcellulose, a low-melting wax, cocoa butter, and the like.Tablets, powders, cachets, lozenges, fast-melt strips, capsules andpills can be used as solid dosage forms containing the active ingredientsuitable for oral administration.

For preparing suppositories, a low-melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first-melted and the activeingredient is dispersed homogeneously therein, as by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, retentionenemas, and emulsions, for example, water or water propylene glycolsolutions. For parenteral injection, liquid preparations can beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral administration can be prepared bydissolving the active ingredient in water and adding suitable colorants,flavors, stabilizing, and thickening agents as desired. Aqueoussuspensions for oral administration can be prepared by dispersing thefinely divided active ingredient in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

The pharmaceutical composition is preferably in unit dosage form. Insuch form, the composition is subdivided into unit doses containingappropriate quantities of the active ingredient. The unit dosage formcan be a packaged preparation, the package containing discretequantities of, for example, tablets, powders, and capsules in vials orampules. Also, the unit dosage form can be a tablet, cachet, capsule, orlozenge itself, or it can be the appropriate amount of any of these inpackaged form.

The quantity of active ingredient in a unit dose preparation may bevaried or adjusted from about 0.1 mg to about 1000.0 mg, preferably fromabout 0.1 mg to about 100 mg. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill inthe art. Also, the pharmaceutical composition may contain, if desired,other compatible therapeutic agents.

In therapeutic treatment or as a method-of-use as an inhibitor of11β-HSD1 or an inhibitor in the production of cortisol in the cell, theactive ingredient is preferably administered orally in a solid dosageform as disclosed above in an amount of about 0.1 mg to about 100 mg perdaily dose where the dose is administered once or more than once daily.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication or patent application were specificallyand individually designated as having been incorporated by reference. Itis understood that the examples and embodiments described herein are forillustrative purposes only, and it will be appreciated that theinvention is susceptible to modification, variation and change withoutdeparting from the proper scope or fair meaning of the appended claims.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound of Formula (Iq⁵)

wherein: R¹ is (a) absent or (b) is selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₃)alkoxy(C₁-C₃)alkoxy, and(C₁-C₃)alkoxy(C₁-C₃)alkyl, each of which is optionally substituted withup to four groups independently selected from fluorine, cyano, oxo, R⁴,R⁴O—, (R⁴)₂N—, R⁴O₂C—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—,(R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—,(R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—,(R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—,R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—,R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—,(R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—,R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—,R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—,(R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, heterocyclyl,heteroaryl, arylamino and heteroarylamino; A¹ is (a) a bond, or (b)(C₁-C₃)alkylene or CH₂CH₂O, wherein the oxygen is attached to Cy¹, orCH₂C(═O), wherein the carbonyl carbon is attached to Cy¹; Cy¹ is aryl,heteroaryl, monocyclic cycloalkyl or monocyclic heterocyclyl, each ofwhich is optionally substituted with 1 to 4 groups independentlyselected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino,hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; the pyridazine ring inFormula Iq⁵ is optionally substituted with 1 to 4 groups independentlyselected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino,hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkyl-alkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkyl-alkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; E is (a) a bond or (b)(C₁-C₃)alkylene or (C₁-C₂)alkylenyloxy, wherein the O is attached to R²,each of which is optionally substituted with 1 to 4 groups independentlyselected from methyl, ethyl, trifluoromethyl and oxo; R² is(C₁-C₆)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl, each ofwhich is optionally substituted with up to 4 groups independentlyselected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino,hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkylalkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cyclo-alkylalkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl, oxo,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl anddi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl; R³ is selected from(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₅)cycloalkyl(C₁-C₄)alkyl, (C₁-C₃)alkoxy(C₁-C₃)alkoxy, and(C₁-C₃)alkoxy(C₁-C₃)alkyl, each of which is optionally substituted withup to four groups independently selected from fluorine, cyano, oxo, R⁴,R⁴O—, (R⁴)₂N—, R⁴O₂C—, R⁴C(═O)O—, R⁴S, R⁴S(═O)—, R⁴S(═O)₂—, R⁴C(═O)NR⁴—,(R⁴)₂NC(═O)—, (R⁴)₂NC(═O)O—, (R⁴)₂NC(═O)NR⁴—, R⁴OC(═O)NR⁴—,(R⁴)₂NC(═NCN)NR⁴—, (R⁴O)₂P(═O)O—, (R⁴O)₂P(═O)NR⁴—, R⁴OS(═O)₂NR⁴—,(R⁴)₂NS(═O)₂O—, (R⁴)₂NS(═O)₂NR⁴—, R⁴S(═O)₂NR⁴—, R⁴S(═O)₂NHC(═O)—,R⁴S(═O)₂NHC(═O)O—, R⁴S(═O)₂NHC(═O)NR⁴—, R⁴OS(═O)₂NHC(═O)—,R⁴OS(═O)₂NHC(═O)O—, R⁴OS(═O)₂NHC(═O)NR⁴—, (R⁴)₂NS(═O)₂NHC(═O)—,(R⁴)₂NS(═O)₂NHC(═O)O—, (R⁴)₂NS(═O)₂NHC(═O)NR⁴—, R⁴C(═O)NHS(═O)₂—,R⁴C(═O)NHS(═O)₂O—, R⁴C(═O)NHS(═O)₂NR⁴—, R⁴OC(═O)NHS(═O)₂—,R⁴OC(═O)NHS(═O)₂O—, R⁴OC(═O)NHS(═O)₂NR⁴—, (R⁴)₂NC(═O)NHS(═O)₂—,(R⁴)₂NC(═O)NHS(═O)₂O—, (R⁴)₂NC(═O)NHS(═O)₂NR⁴—, spirocycloalkyl;heterocyclyl (optionally substituted with alkyl, haloalkyl, halogen oroxo), heteroaryl (optionally substituted with alkyl, haloalkyl, alkoxy,alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro,cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido,N,N-dialkyl-substituted amido, or oxo), arylamino (optionallysubstituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen,trifluoromethyl, dialkylamino, nitro, cyano, CO₂H, CONH₂,N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) andheteroarylamino (optionally substituted with alkyl, haloalkyl, alkoxy,alkylthio, alkylsulfonyl, halogen, trifluoromethyl, dialkylamino, nitro,cyano, CO₂H, CONH₂, N-monoalkyl-substituted amido,N,N-dialkyl-substituted amido, or oxo); and R⁴ is independently selectedfrom H, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl and (C₁-C₆)alkoxy(C₁-C₆)alkyl; or a pharmaceuticallyacceptable salt, enantiomer or diastereomer thereof.
 2. The compound ofclaim 1, wherein the compound is of Formula (Is⁵):

or a pharmaceutically acceptable salt thereof; wherein: n is 0, 1, 2 or3; and G¹ is fluorine, chlorine, bromine, iodine, cyano, nitro, amino,hydroxy, carboxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,hydroxy(C₃-C₆)cycloalkyl, (C₄-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl,halo(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₆)cycloalkyl(C₂-C₄)alkynyl, halo(C₁-C₆)alkyl,halo(C₃-C₆)cycloalkyl, halo(C₄-C₇)cycloalkylalkyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkoxy, (C₄-C₇)cycloalkylalkoxy, halo(C₁-C₆)alkoxy,halo(C₃-C₆)cycloalkoxy, halo(C₄-C₇)cycloalkylalkoxy, (C₁-C₆)alkylthio,(C₃-C₆)cycloalkythio, (C₄-C₇)cycloalkylalkylthio, halo(C₁-C₆)alkylthio,halo(C₃-C₆)cycloalkythio, halo(C₄-C₇)cycloalkylalkylthio,(C₁-C₆)alkanesulfinyl, (C₃-C₆)cycloalkanesulfinyl,(C₄-C₇)cycloalkylalkanesulfinyl, halo(C₁-C₆)alkanesulfinyl,halo(C₃-C₆)cycloalkanesulfinyl, halo(C₄-C₇)cycloalkylalkanesulfinyl,(C₁-C₆)alkanesulfonyl, (C₃-C₆)cycloalkanesulfonyl,(C₄-C₇)cycloalkyl-alkanesulfonyl, halo(C₁-C₆)alkanesulfonyl,halo(C₃-C₆)cycloalkanesulfonyl, halo(C₄-C₇)cycloalkyl-alkanesulfonyl,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, H₂NCO, H₂NSO₂,(C₁-C₆)alkylaminocarbonyl, di(C₁-C₆)alkylaminocarbonyl,(C₁-C₃)alkoxy(C₁-C₃)alkylaminocarbonyl, heterocyclylcarbonyl,(C₁-C₆)alkylaminosulfonyl, di(C₁-C₆)alkylaminosulfonyl,heterocyclylsulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, heteroaryl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl amino(C₂-C₆)alkoxy,(C₁-C₆)alkylamino(C₂-C₆)alkoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy,(C₁-C₆)alkylcarbonyl, (C₃-C₆)cycloalkylcarbonyl,(C₃-C₆)cycloalkylaminocarbonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl,di(C₃-C₆)cycloalkylaminocarbonyl, (C₃-C₆)cycloalkylaminosulfonyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminosulfonyl,di(C₃-C₆)cycloalkylaminosulfonyl, cyano(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,di(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl,{(C₃-C₆)cycloalkyl}{(C₁-C₆)alkyl}aminocarbonyl(C₁-C₆)alkyl ordi(C₃-C₆)cycloalkylaminocarbonyl(C₁-C₆)alkyl.
 3. The compound of claim2, wherein: n is 0, 1, 2 or 3; G¹ is (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, halogen, cyano or nitro; the ringcarbon atoms in the pyridazine ring in Formula Is⁵ are independentlyoptionally substituted with fluorine, chlorine, cyano, amino,(C₁-C₄)alkyl, (C₃-C₄)cycloalkyl, (C₃-C₄)cycloalkyl(C₁-C₂)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, CONH₂,(C₁-C₄)alkylaminocarbonyl, di(C₁-C₄)alkylaminocarbonyl,(C₃-C₄)cycloalkylaminocarbonyl,{(C₁-C₄)alkyl}{(C₃-C₄)cycloalkyl}aminocarbonyl or(C₁-C₄)alkylcarbonylamino; R¹ is methyl or ethyl; and R² is phenyloptionally substituted with 1, 2 or 3 substituents selected from halo,cyano, CONH₂, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl and SO₂Me; and R³ isMeSO₂NHCH₂CH₂CH₂, H₂NC(═O)CH₂CH₂, H₂NC(═O)CMe₂CH₂, 3-hydroxypropyl,3-hydroxy-3-methylbutyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl and2-cyano-2-methylpropyl.
 4. The compound of claim 1, wherein the compoundis selected from one of the following Formulas:

or a pharmaceutically acceptable salt thereof.
 5. A method of treating asubject with a disease or disorder selected from diabetes mellitus,obesity, metabolic syndrome, prothrombotic state, proinflammatory state,glucose intolerance, hyperglycemia, hypertension, hyperlipidemia,insulin resistance, dyslipidemia, atherosclerosis, lipodystrophy,osteoporosis, glaucoma, Cushing's syndrome, Addison's disease, visceralfat obesity associated with glucocorticoid therapy, depression, anxiety,dementia, cognitive decline, polycystic ovarian syndrome, hypergonadism,tuberculosis, leprosy, psoriasis, to promote wound healing,hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDLlevels, vascular restenosis, pancreatitis, abdominal obesity, coronaryheart disease, peripheral vascular disease, hyperinsulinemia, viraldiseases, and Syndrome X, comprising the step of administering to thesubject an effective amount of the compound in claim
 1. 6. Apharmaceutical composition comprising: i) a pharmaceutically acceptablecarrier or diluent; and ii) the compound in claim 1; or apharmaceutically acceptable salt, enantiomer or diastereomer thereof. 7.The compound of claim 1, wherein the compound is of the formula:(S)-3-((S)-1-(4-(5-chloro-6-methylpyridazin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one;(S)-3-((S)-1-(4-(6-chloro-3-methylpyridazin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one;(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-(2-hydroxypropan-2-yl)pyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one;N-tert-butyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridazine-3-carboxamide;N-tert-butyl-6-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridazine-3-carboxamide;N-cyclopropyl-6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)pyridazine-3-carboxamide;6-(4-((S)-1-((R)-6-(2-cyano-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N-cyclopropylpyridazine-3-carboxamide;(R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one;(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(pyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one;(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one;(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one;2,2-dimethyl-3-((R)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile;(R)-6-(methoxymethyl)-3-((S)-1-(4-(6-methylpyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one;6-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid dimethylamide;6-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid;6-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid methylamide; or6-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylicacid amide; or a pharmaceutically acceptable salt thereof.